we are glad to greet you in the international school...
TRANSCRIPT
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We are glad to greet you in the International School-Seminar on Computer-Aided
Molecular Design (CAMD2016), which takes place in Kazan, Russia, from 18th to 20th
May, 2016.
Computational technologies have been proven to successfully assist chemists in
design of new chemical moieties. It was shown numerous times that usage of
chemoinformatics, bioinformatics and molecular modeling tools substantially reduces
costs in drug design. This School-seminar is devoted to usage of quantum chemical, force-
field and chemoinformatics modeling in molecular and material design. The main goal of
the event is the development and promoting of computational approaches usage in
molecular and material design through education and making conditions for sharing of
scientific experience.
The main topics of the School-seminar are:
- Chemoinformatics-assisted technologies in molecule design,
- Force-field modeling usage in understanding of biochemical processes and
new chemical entities design,
- Quantum chemistry approaches in compound and material design,
- Computer-aided technologies in chemical synthesis.
The event gathers specialists from different fields of computational chemistry to
make presentation of their findings or overview of special field. The School-seminar
includes:
- Lectures on different approaches in molecule and material design,
- Key-note presentations on new developments in the field,
- Oral presentations by young scientists.
GENERAL INFORMATION
ORGANIZERS
Kazan (Volga region) Federal University
Russian Science Foundation
D.I. Mendeleev Chemical Society of Republic of Tatarstan
ORGANIZING COMMITTEE
Chairmen of the Organizing Committee:
Prof. Igor S. Antipin (Kazan, Russia)
Prof. Alexandre Varnek (Strasbourg, France)
Scientific Secretary: T.I. Madzhidov (Kazan, Russia)
Local Committee:
A.R.Gabdullina M.A. Kazymova R.I. Nugmanov
A.I. Lin T.R. Gimadiev M.V. Glavatskikh
N.R. Khafizov O.P. Varlamov N.I. Ivanova
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INTERNATIONAL ADVISORY COMMITTEE
Prof. J. Gasteiger (University of Erlangen, Germany)
Prof. A. Tropsha (University of North Carolina, USA)
Prof. D. Horvath (CNRS, France)
Prof. V. G. Tsirelson (Mendeleev University of Chemical Technology, Russia)
Prof. H. Senderowitz (Bar Ilan University, Israel)
Prof. Y. Ustynyuk (Moscow State University, Russia)
Prof. G. Marcou (University of Strasbourg, France)
Prof. V. Torbeev (University of Strasbourg, France)
Dr.Sci. V.P. Solov'ev (Institute of Physical Chemistry and Electrochemistry, Russia)
Dr. P. Polishchuk (Palacký University of Olomouc, Czech Republic)
Dr. O. Klimchuk (University of Strasbourg, France)
SCIENTIFIC PROGRAM
The program of the International School-Seminar on Computer-Aided Molecular
Design includes 7 lectures, 8 key-note presentations and 17 oral reports. The Round Table
for International Advisory Committee will be held as pre-conference event May 18, 2016.
OFFICIAL LANGUAGE
The official language is English. No translation is provided.
OFFICE OF THE ORGANIZING COMMITTEE
The office of the organizing committee is located at A.M. Butlerov Chemical
Institute old building, Auditorium No. 218. Participants will be able to use telephone,
Internet and printing facilities there.
VENUE
The event will be held in the A.M. Butlerov Chemical Institute laboratory (new)
building (Lobachevskogo St. 1). Lectures, key-note and oral presentations as well as
registration and the ceremonies will take place in the Hall No. 206 of the new building.
The Round Table for International Advisory Committee will start in the Hall 218 of the
Old Building of the Institute.
COFFEE-BREAKS
Coffee breaks are free for all participants and will take place in the Hall No. 210.
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PROGRAM
of International School-Seminar on Computer-Aided Molecular Design May 18, 2016
13:00-18:00 Round table for International Advisory Committee (Hall 218 of Old Building)
May 19, 2016
8.00-9.00 Registration
9.00-9.15 Opening Ceremony
Chair of the session - A. Varnek
9.15-9.55 Lecture 1 /
A. Tropsha (USA)
Drug repurposing by data mining
9.55-10.35 Lecture 2 /
J. Gasteiger (Germany)
Learning about chemical reactions and the design of
organic syntheses
10.35-11.00 Coffee - break
Chair of the session – J. Gasteiger
11.00-11.40 Lecture 3 /
A. Varnek (France)
Hunting novel antithrombotics: lessons of practical
chemoinformatics
11.40-11.50 Oral Presentation 1 /
A. Lin (Russia),
O. Klimchuk (France)
Assessment of optimal reaction conditions in reactions of
catalytic hydrogenation
11.50-12.00 Oral Presentation 2 /
S. Lushchekina (Russia)
Molecular modeling for understanding complex kinetic
processes in cholinesterases
12.00-14.00 Lunch
Chair of the session – D. Horvath
14.00-14.30 Key-note presentation 1/
H. Senderowitz (Israel)
A reliable computational workflow for the selection of
optimal screening libraries
14.30-15.10 Key-note presentation 2 /
I. Baskin (Russia)
Dimensionality reduction in chemoinformatics. Generative
topographic mapping
15.10-15.20 Oral Presentation 3 /
M. Glavatskikh (Russia)
Predictive models for diiodine basicity scale of halogen
bond
15.10-15.20
Oral Presentation 4 /
O. Titov (Russia)
Quadrupole-based correction for halogen bonding
description in Autodock-XB scoring function
15:30-16:00 Coffee - break
Chair of the session – V. Tsirelson
16.00-16.30 Key-note presentation 3 /
G. Marcou (France)
QSAR and GTM study of phenotypic anti-malarial
compounds
16.30-17.00 Key-note presentation 4 /
V. Solov'ev (Russia)
Thermodynamics of hydrogen bonding: from experimental
measurements to structure-property modeling
17.00-17.10 Oral Presentation 5 /
T. Makarova (Russia)
Molecular-dynamics study of allostric pathways in
bacterial ribosome
17.10-17.20 Oral presentation 6 /
T. Gimadiev (Russia)
Predicting of reactivity for biorthogonal reactions of
sydnones heterocycles with alkynes
17.20-17.30 Oral presentation 7 /
S. Dzhabieva (Russia)
Prediction of benzotriazole derivatives retention factor
using molecular structure descriptors
17.30-17.40 Oral presentation 8 /
N. Akberova (Russia)
Molecular Dynamics of an anti-DNA antibody Fab-
fragment associated with a dsDNA fragment
17.40-17.50 Oral presentation 9 /
R. Ayupov (Russia)
Analysis of molecular dynamics of SaPHF protein
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May 20, 2016
Chair of the session – R. Nazmutdinov
9.00-9.40 Lecture 4 /
V. Tsirelson (Russia)
The Atomic and Molecular Interactions: What Can We
Learn from Electron Density?
9.40-10.20 Lecture 5 /
Yu. Ustynyuk (Russia)
Highly selective artificial receptors for the recognition and
binding of cations and anions: computer design, synthesis
and coordination properties.
10.20-10.50 Coffee - break
Chair of the session - H. Senderowich
10.50-11.30 Lecture 6 /
R. Nazmutdinov
(Russia)
Molecular modeling of redox-processes at electrochemical
interfaces: old problems and new challenges
11.30-12.00 Key-note presentation 5/
P. Polishchuk (Czech
Republic)
Interpretation of QSAR models: past and present
12.00-14.00 Lunch
Chair of the session – G. Marcou
14.00-14.40 Lecture 7 /
M. Balakina (Russia)
Self-assembly in design of quadratic nonlinear optical
polymer materials
14.40-15.00 Key-note presentation 6 /
D. Horvath (France)
Conformational Sampling & Docking: State-of-the-art and
Challenges
15.00-15.30 Key-note presentation 7 /
V. Torbeev (France)
Understanding protein function by total chemical synthesis
15.30-16.00 Key-note presentation 8 /
T. Madzhidov (Russia)
Prediction of tautomeric equilibria: QSAR vs quantum
chemistry
16.00-16.30 Coffee - break
Chair of the session – M. Balakina
16.30-16.40 Oral presentation 11 /
T. Salah (Algeria)
Conceptual DFT and molecular docking combination for
understanding ligand-receptor binding mode
16.40-16.50 Oral presentation 12 /
S. Shermukhamedov
(Russia)
Does nickel segregation occur in bimetallic NiCu
nanoparticles?
16.50-17.00 Oral presentation 13 /
A. Loginova (Russia)
The reactivity of –O–Au–O– chain structures on the model
Au(321) surface: a computational study
17.00-17.10 Oral presentation 14 /
N. Burmistrova (Russia)
Aromatic amine in design of fluorescent probe based on
photoinduced electron transfer
17.10-17.20 Oral presentation 15 /
N. Nekrasova (Russia)
Quantum chemistry approach to studying of
tetrahydroquinolines adsorption under liquid
chromatography conditions
17.20-17.30 Oral presentation 16 /
M. Glagolev (Russia)
Multi-scale simulation of hypercrosslinked polystyrene
networks
17.30-17.40 Oral presentation 17 /
R. Nugmanov (Russia)
Reaction validation and standartization workflow
17.40-17.50 Closing ceremony
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Abstracts
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A. Tropsha DRUG REPURPOSING BY DATA MINING UNC Eshelman School of Pharmacy, CB # 7568 Beard Hall, UNC-
Chapel Hill, Chapel Hill, NC 27599, USA
[email protected] There have been recent reports on application of text mining and cognitive computing to
extracting terms and assertions relevant to both therapeutic and adverse effects of drugs from
unstructured texts in publications, Facebook and Twitter exchanges, and other internet sources
(Freifeld et al., 2014; Spangler et al., 2014; Yom-Tov & Gabrilovich, 2013). In parallel, there have
been also publications from our and other groups on the successful use of non-laboratory data (such
as assertions linking two terms, e.g., a chemical name and specific bioactivity) for building rigorous
and externally validated Quantitative Structure-Activity Relationship (QSAR) models (Baker,
Fourches, & Tropsha, 2015; Low et al., 2015). Finally, there have been multiple reports on the use
of QSAR or structure-based docking models for virtual screening of chemical libraries to predict
novel bioactivity for known drugs (Hajjo, Setola, Roth, & Tropsha, 2012; Varnek & Tropsha,
2008).
The aforementioned publications provide examples of computational studies in
complimentary but disconnected fields. I will discuss a computational workflow that ties together
tools for text mining of observational human data, biological network mining, molecular modeling
of biological drug targets, and confirmatory exploration of specialized medical literature and
patient data. This workflow integrates uniquely a range of data (and associated tools) from man to
molecules to man with the goal of in silico discovery of novel drug-target and drug-disease
associations. I will provide examples that illustrate elements of this workflow including
applications to anti-Alzheimer and anti-cancer drug discovery, toxicity prediction, and the
identification of drugs that may cause Stevens-Johnson Syndrome.
1. Baker, N. C., Fourches, D., & Tropsha, A. (2015). Drug Side Effect Profiles as Molecular
Descriptors for Predictive Modeling of Target Bioactivity. Molecular Informatics, 34(2-3),
160–170.
2. Fourches, D., Barnes, J. C., Day, N. C., Bradley, P., Reed, J. Z., & Tropsha, A. (2010).
Cheminformatics analysis of assertions mined from literature that describe drug-induced
liver injury in different species. Chemical Research in Toxicology, 23(1), 171–183.
3. Freifeld, C. C., Brownstein, J. S., Menone, C. M., Bao, W., Filice, R., Kass-Hout, T., &
Dasgupta, N. (2014). Digital Drug Safety Surveillance: Monitoring Pharmaceutical
Products in Twitter. Drug Safety, 37(5), 343–350.
4. Hajjo, R., Setola, V., Roth, B. L., & Tropsha, A. (2012). Chemocentric informatics
approach to drug discovery: identification and experimental validation of selective estrogen
receptor modulators as ligands of 5-hydroxytryptamine-6 receptors and as potential
cognition enhancers. Journal of Medicinal Chemistry, 55(12), 5704–19.
5. Low, Y., Caster, O., Bergvall, T., Fourches, D., Zang, H., Norén, G. N., … Tropsha, A.
(2015). Cheminformatics-Aided Pharmacovigilance: Application to Stevens Johnson
Syndrome. Journal of the American Medical Informatics Association, In press.
6. Spangler, S., Myers, J. N., Stanoi, I., Kato, L., Lelescu, A., Labrie, J. J., … Comer, A.
(2014). Automated hypothesis generation based on mining scientific literature. In
Proceedings of the 20th ACM SIGKDD international conference on Knowledge discovery
and data mining - KDD ’14 (pp. 1877–1886). New York, New York, USA: ACM Press.
7. Varnek, A., & Tropsha, A. (Eds.). (2008). Chemoinformatics Approaches to Virtual
Screening. Cambridge: Royal Society of Chemistry.
8. Yom-Tov, E., & Gabrilovich, E. (2013). Postmarket Drug Surveillance Without Trial Costs:
Discovery of Adverse Drug Reactions Through Large-Scale Analysis of Web Search
Queries. Journal of Medical Internet Research, 15(6), e124.
7
J. Gasteiger
LEARNING ABOUT CHEMICAL REACTIONS
AND THE DESIGN OF ORGANIC SYNTHESES Computer-Chemie-Centrum, University of Erlangen-Nuremberg, D-
91052 Erlangen, Germany
Chemical reactions play a major role in chemistry, from running processes in industrial
plants, through laboratory reactions, to the breakdown of structures in the mass spectro-meter.
However, whereas the processing of molecular structures by chemoinformatics methods has
progressed quite far, the computer handling of chemical reactions leaves much to be desired [1].
Databases on chemical reactions are notoriously incomplete, usually reporting only parts of the
essential features of chemical reactions, often not containing information on solvents,
temperature, reaction time or side reactions [2]. Organic chemists have developed a series of
concepts such as partial atomic charges, inductive, resonance, polarizability, or steric effects to
rationalize their observations on chemical reactions. We have developed methods for rapidly
calculating these effects and have used them to model reaction data such as those on gas phase
reactions, pKa values, and kinetic data on the hydrolysis of amides. These effects have also
been found useful for classifying reactions in reaction databases [3].
In the beginning of the field of chemoinformatics much work was devoted to Computer-
Assisted Synthesis Design (CASD). As a side effect, this work led to the development of
important databases in chemistry. Our efforts in the field will be illustrated with the
development ofv the systems EROS, WODCA and THERESA.
Recently methods have been developed for the prediction of how easily it will be to
synthesize an organic compound [4].
1. W. Warr, Mol. Inform., 2014, 33, 469-476.
2. A. Parlow, C. Weiske, J. Gasteiger, J. Chem. Inf. Comput. Sci.,1990, 30, 400-402.
3. J. Gasteiger, J. Comput. Aided. Mol. Des., 2007, 21, 33-52.
4. J. Gasteiger, Nature Chemistry, 2015, 7, 619-620.
8
A. Varnek
HUNTING NOVEL ANTITHROMBOTICS: LESSONS
OF PRACTICAL CHEMOINFORMATICS
Laboratory of chemoinformatics, University of Strasbourg, 1 rue Blaise
Pascal, 67000 Strasbourg, France
In this presentation we describe a collaborative project resulted in successful computer-aided
design of new antithrombotics – compounds which reduce the formation of blood clots [1-3].
Our goal was to design the antagonists of integrin αIIbβ3 - a protein responsible for the
interaction of platelets with fibrinogen leading to clots formation. The chemoinformatics workflow
involved several “classical” steps: data preparations, structure-activity modelling, generation and
screening of virtual library steps as well as ADME/tox assessment of selected hits. Eight compounds
suggested theoretically have been synthesized and experimentally tested. All of them display high
binding and anti-aggregation activities similar or even higher than that of tirofiban, commercial drug
molecule.
Weak and strong points of different computational approaches (QSAR modeling, 2D and 3D
pharmacophores, shape and filed-based similarity ligand-to-protein docking) used in this study will be
discussed in details.
I thank T. Khristova, P. Polishchuk, V. Kuzmin, A. Krysko, my partners from the Bogatsky
Physico-Chemical Institute (Odessa, Ukraine), for their contribution to this project.
1. P. G. Polishchuk, G. V. Samoylenko, T. M. Khristova, O. L. Krysko, T. A. Kabanova, V. M.
Kabanov, A. Yu. Kornylov, O. Klimchuk, T. Langer, S. A. Andronati, V. E. Kuz’min, A. A. Krysko,
A. Varnek, J. Med. Chem., 2015, 58 (19), pp 7681–7694
2. A.A. Krysko, G. V. Samoylenko, P. G. Polishchuk, S. A. Andronati, T. A. Kabanova, T. M.
Khristova, V. E. Kuz'min, V. M. Kabanov, Olga L. Krysko, A.A. Varnek and R. Ya. Grygorash.
Bioorganic & Medicinal Chemistry Letters, 2011, 21, 5971–5974
3. Krysko, A. A Samoylenko, G. V; Polishchuk, P.G.; Fonari, M. S; Kravtsov, V. C; Andronati, S. A;
Kabanova, T. A; Lipkowski, J; Khristova, T. M; Kuz'min, V. E; Kabanov, V. M; Krysko, O. L;
Varnek, A. A. Bioorganic & Medicinal Chemistry, 2013, 21(15), 4646-4661
9
O. Klimchuk1
A. I. Lin2
T.I.Madzhidov2
R. I. Nugmanov2
I. Antipin2
A. Varnek1
ASSESSMENT OF OPTIMAL CONDITIONS IN
REACTIONS OF CATALYTIC HYDROGENATION 1 University of Strasbourg, 4, Blaise Pascal str., 67081, Strasbourg,
France 2 A.M. Butlerov Chemical Institute, Kazan Federal University,
Kremlevskaya 18, 420008, Kazan, Russia
Synthesis of complex structures became a central problem of organic chemistry. Recently it
became clear that computational technologies could come to the scene and assist chemists in
prediction of optimal solvents, catalysts and other conditions. However, only first steps were done
in this direction. Recently, Struebing et al.1 published a mixed quantum mechanics – linear free
energy relationship based approach for prediction of optimal solvent for bimolecular reactions.
Marcou et al.2 built classification model to predict optimal type of solvent and type of catalyst for
Michael reaction using machine learning methods.
New approach that extracts expert knowledge on optimal conditions of deprotection
reactions from large amount of raw and “big” reaction data in a fully automatic workflow will be
presented. The method is based on Condensed Graph of Reaction 3 approach. It was applied to more
than 142000 hydrogenation reactions taken from Reaxys database. The approach allows to build in
a fully automatic way Green’s Reactivity Charts4 that could be updated as new reaction appears in
database. Unlike ordinary Charts published in the book4, our tables are based on analysis of all the
information existing in the database with explicitly stated rules. Moreover, advanced analysis could
be performed and more detailed information could be extracted. The approach also could provide
information on selectivity of group deprotection and protective group transformation.
About 100 possibilities of molecule protection were considered. Most of information on the
protective group’s reactivity from Charts4 is supported by our statistical analysis. However, there
are some contradictions in about 5% of all cases. Also, the dependences of the reactivity for the
most popular protective groups (Benzyl in phenols, Benzyl in alcohols, TBDMS in alcohols, N-
Acetyl amide, t-Butyl carbamate and Benzyl carbamate) on the presence of acid and catalytic
poison have been analyzed. As expected, in the presence of an acid the protective group’s reactivity
increases while in the presence of catalytic poison it decreases. The advantage of this analysis is the
possibility to assess the protective group's ability to be cleaved in the presence of particular
substance (e.g., Na2CO3).
1. Struebing, H. et al. Nat. Chem. 5, 952–957 (2013).
2. Marcou, G., et al J. Chem Inf. Model. 55, 239-250 (2015).
3. Varnek A., Fourches D., Hoonakker F., Solov_ev V.P. // J. Comput. Aided. Mol. Des. 2005,
19, 693 – 703.
4. Wuts, P. G. M. Greene's Protective Groups in Organic Synthesis; Wiley, 2014.
The research was supported by Russian Scientific Foundation, grant 14-43-00024. We thank the
Reaxys database (Elsevier, Netherlands) for providing us with the experimental reaction data and
ChemAxon company for the software license.
10
S.V. Lushchekina1,2
P. Masson3
A.V. Nemukhin1,4
E.E. Nikolsky2,3
S.D. Varfolomeev1,4
MOLECULAR MODELING FOR UNDERSTANDING
COMPLEX KINETIC PROCESSES IN
CHOLINESTERASES 1 Emanuel Institute of Biochemical Physics of the Russian Academy of
Sciences, Moscow, Russia; 2 Arbuzov Institute of Organic and Physical Chemistry of Russian
Academy of Sciences, Kazan, Russia; 3 Institute of Fundamental Medicine and Biology, Kazan Federal
University, Kazan, Russia; 4 Chemistry Department of Lomonosov Moscow State University,
Moscow, Russia
[email protected] Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are targets for several
directions of drug design: development of drugs against Alzheimer’s disease (AD) and myasthenia
gravis, and development of antidotes against poisoning by organophosphorus (OP) compounds.
Novel inhibitors of AChE designed as anti-AD agents must be able to cross the blood-brain barrier,
and cause less side effects compared to existing drugs. A recent study demonstrated that inhibitors of
the peripheral anionic site of AChE also reduce formation of β-amyloid plaques in brain [1]. For
treatment of myasthenia gravis inhibitors must not affect brain AChE and act only at neuromuscular
junction to restore muscle functionality. Recently described compound C-547 shows a complex
binding kinetics, i.e., slow-binding inhibition of type B [2,3]. This results in high selectivity and
increased residence time on AChE, that improves pharmacological effect and reduce side effects. To
describe such complex mechanisms of target-drug binding, molecular docking followed by various
methods of molecular dynamics were used. Protein-protein docking and accelerated molecular
dynamics helped to demonstrate the role of AChE in promoting β-amyloid aggregation and
development of AD. Steered molecular dynamics simulations and free energy profile calculations
revealed step-by-step the mechanism of C-547 binding to AChE and its quasi-irreversible nature.
Molecular modeling results were confirmed by X-ray study.
Regarding OP poisoning of AChE, the sister enzyme BChE serves as a stoichiometric
bioscavenger by covalently binding a fraction of the toxicant dose. Active site mutation G117H
leads to spontaneous reactivation of OP-inhibited BChE. Thus, the enzyme has acquired a
promiscuous phosphotriesterase activity and acts as a catalytic bioscavenger [4]. Molecular
modeling of mechanism of this reaction with QM/MM method allows to comparison of pathways for
reactivation and aging processes in OP-inhibited G117H BChE and the hypothetical reactivation of
wild-type enzyme. Comparison of energy barriers provides evidence that histidine 117 introduced in
the active site acts in lowering energy barriers of reactivation reaction states, leading to acceleration
of reactivation kinetics, stabilization of intermediate and products, and improving the process
thermodynamics.
1. Semenov V. et al. ChemMedChem, 2015, 10: 1863-1874
2. Masson P., Lushchekina S. Arch. Biochem. Biophys., 2016, 593: 60-68.
3. Kharlamova A., Lushchekina S. et al. Biochemical Journal, 2016, 473: 1225-1236.
4. Masson P., Lushchekina S. Chemico-Biological Interactions, 2016, in press.
Work was supported by Russian Foundation for Basic Research, project 13-00-40286-K and
Russian Scientific Foundationm, project 14-50-00014.
11
Y. Gilad,1
K. Nadassy2,
H. Senderowitz1
A RELIABLE COMPUTATIONAL WORKFLOW FOR
THE SELECTION OF OPTIMAL SCREENING
LIBRARIES 1Department of Chemistry, Bar Ilan University, Ramat Gan, 5290002, Israel
2Dassault Systèmes BIOVIA, 334 Cambridge Science Park, Cambridge CB4
0WN, UK.
[email protected] The experimental screening of compound collections is a common starting point in many
drug discovery projects. Successes of such screening campaigns critically depend on the quality of
the screened library. Many libraries are currently available from different vendors yet the selection
of the optimal screening library for a specific project is challenging. We have devised a novel
workflow for the rational selection of project-specific screening libraries. The workflow accepts as
input a set of virtual candidate libraries and applies the following steps to each library: (1) data
curation; (2) assessment of ADME/T profile; (3) assessment of the number of promiscuous binders/
frequent HTS hitters; (4) assessment of internal diversity; (5) assessment of similarity to known
active compound(s) (optional); (6) assessment of similarity to in-house or otherwise accessible
compound collections (optional). For ADME/T profiling, Lipinski’s and Veber’s rule-based filters
were implemented and a new blood brain barrier permeation model was developed and validated
(85% and 74% success rate for training set and test set, respectively). Diversity and similarity
descriptors which demonstrated best performances in terms of their ability to select either diverse or
focused sets of compounds from three databases (Drug Bank, CMC and CHEMBL) were identified
and used for diversity and similarity assessments. The workflow was used to analyze nine common
screening libraries available from six vendors. The results of this analysis are reported for each
library providing an assessment of its quality. Furthermore, a consensus approach was developed to
combine the results of these analyses into a single score for selecting the optimal library under
different scenarios. The current workflow was implemented using the Pipeline Pilot software yet due
to the usage of generic components, it can be easily adapted and reproduced by computational
groups interested in rational selection of screening libraries. Furthermore, the workflow could be
readily modified to include additional components. This workflow has been routinely used in our
laboratory for the selection of libraries in multiple projects and consistently selects libraries which
are well balanced across multiple parameters.
12
P. Polishchuk INTERPRETATION OF QSAR MODELS: PAST AND
PRESENT
Institute of Molecular and Translational Medicine, Faculty of Medicine
and Dentistry, Palacky University, Hněvotínská 1333/5, Olomouc,
Czech Republic
Interpretation of QSAR models may bring many benefits to researchers. It may help to
understand the underlying structure-property relationship, explain possible mechanism of actions,
activity and selectivity of chemical compounds and much more. This knowledge may also be used
for rational design of new compounds with a desired set of properties. However, interpretation of
QSAR models are not always clear and straightforward.
Traditionally, interpretation of QSAR models consists of two parts interpretability of
machine learning methods and interpretability of descriptors. First QSAR models used descriptors
with clear structural (Free-Wilson models) or physico-chemical meaning (Hansch models). In
combination with interpretable machine learning methods (ordinary regression, partial least squares,
decision trees) this provides clear interpretation of obtained QSAR models. However, simple linear
models and decision tree models have low predictive ability and other drawbacks. Therefore,
research interests were shifted towards more complex models with higher predictive power: support
vector machine, random forest, neural nets. These models cannot be easily interpreted due to their
complex nature and are considered as “black boxes”. Different approaches for their interpretation
were proposed. However, none of them became popular in the QSAR community. Several
interpretation approaches which can be applied for models based on any machine learning method
were also developed: sensitivity analysis, variable importance, partial derivatives. The last one
became very popular in recent years for interpretation SVM, RF and other models.
Almost all developed interpretation approaches follow the “model → descriptor contributions
→ interpretation” paradigm and thus they require interpretable descriptors for models building that
can restrict predictivity of obtained models. Recently several new approaches of structural
interpretation were proposed which follow the “model → interpretation” paradigm and don’t depend
on the used descriptors and machine learning methods: similarity maps, universal structural
interpretation and computational matched molecular pairs. This makes predictivity and
interpretability of QSAR models closer than never before and may open new era in QSAR modeling.
13
T. Makarova
MOLECULAR-DYNAMICS STUDY OF ALLOSTRIC
PATHWAYS IN BACTERIAL RIBOSOME
Chemistry of Natural Compounds Chair, Chemistry Department,
Lomonosov Moscow State University, Street Leninskie Gory, 1,
Moscow, Russia
Allostery, the conformational mutual coherence between spatially removed parts of a
biomolecule and conformational changes transmission throughout specific pathways, is of
significant scientific interest. Allosteric phenomena in proteins are already well-studied by means of
different calculation and experimental methods with revealing of corresponding allosteric pathways.
Our interest is focused on the ribosome, one of the largest and most complicated biomolecule in the
cell. The ribosome is a huge RNA-protein complex which is responsible for polypeptide chains
formation from activated amino acids, thus providing the cell with all proteins. The ribosome is a
target of majority of clinically used antibiotics, so understanding ribosome allosteric rearrangements
is a prerequisite for rational antibacterial drug design.
Though there are numerous evidences of existence of allosteric signal transmission between
rather remote sites in the ribosome computational investigation of these phenomena was started only
recently [1]. One of these potential allosteric connections, namely regulation of elongation factor G
(EF-G) GTPase activity by E-site occupation with tRNA, was selected for molecular-dynamic
simulations study. The large ribosomal subunit E-site is spatially separated from its GTPase center
with about 70 Å [2].
12 trajectories in restricted system from parallelogram cut-out from the large subunit of the
ribosome and 3 trajectories in full-subunit system were performed. The pathway was figured out via
base-base interaction graphs construction following with elimination of side branches. Its structure
appeared to be formed mainly with stacked base-pairs in helices or helix-like structures occasionally
alternating with hydrogen-bond connected elements.
Participation of E-tRNA and P-tRNA in signal transduction was analyzed by means of
comparative analysis. In the absence of E-tRNA a helix-like structure in E-site vicinity is distorted.
That causes destruction of the structure helix 81 tip responsible for connection with further element,
the tip of helix 39. This event leads to distortions throughout all the pathway. P-tRNA, in its turn,
prevents interference of the residue Gm2251 with helix 89 bottom and destruction of its pairing; the
bottom of helix 89 is a key functional region of 23S rRNA due to its participating in hydrogen-bond
connection with helix 39 and being the point where structural (whole-helical) rearrangements begin
from. The correct binding of both E- and P-tRNAs with their sites is indispensable to sustain a stable
and reproducible coherent structure throughout the pathway which is described here. This event is
also accompanied with macrostructural rearrangements concerning entire helix turns and shifts that
appeared to be visible in the whole-subunit model.
1. Makarov G.I. et al. Molecular Dynamics Investigation of a Mechanism of Allosteric Signal
Transmission in Ribosomes. Biochemistry (Moscow), 2015, 80: 1047-1056.
2. P. V. Sergiev et al. Function of the ribosomal E-site: a mutagenesis study. Nucleic Acids
Research, 2015, 33: 6048-6056.
Calculations were performed on “the Lomonosow” Moscow State University supercomputer. This
work was supported by a grant from the Russian Foundation for Basic Researches (14-24-00061).
14
M. Glavatskikh1,2
T. Madzhidov2
V. Solov’ev3
D. Horvath1
G. Marcou1
A. Varnek1,2
PREDICTIVE MODELS FOR DIIODINE BASICITY
SCALE OF HALOGEN BOND
1 Laboratory of Chemoinformatics, University of Strasbourg, Blaise
Pascal Str, 4, Strasbourg, France; 2 Laboratory of Chemoinformatics and Molecular Modeling, Kazan
Federal University, Kremlyovskaya Str, 18, Kazan, Russia; 3 Frumkin Institute of Physical Chemistry and Electrochemistry RAS,
Leninsky prospect Str, 31, Moscow, Russia;
This work is devoted to QSPR (Quantitative Structure-Property Relationship) models building
of Halogen Bond basicity scale pKI2. The scale is based on the experimental 1:1 (B:I2) complexation
constant logKI2 of organic compounds (B) with diiodine (I2) as a reference halogen-bond donor in
alkanes at 298 K. Models based on ISIDA local descriptors were performed using Support Vector
Machine (SVM) and Multiple Linear Regression (eMLR) methods on a set of 598 organic
compounds. A consensus model returning the mean of values predicted by the most successful
individual SVM models, based on various ISIDA fragmentation schemes, and including applicability
domain assessment strategies (bounding box, standard deviation of consensus prediction). This model
has then been challenged on the external test set of 11 polyfunctional compounds, for which
unambiguous assignment of the measured effective complexation constant could not be assigned to
either of halogen acceptor site. Developed consensus model was used to predict individual logKI2 of
each acceptor sites followed by the prediction of an effective complexation constant with the help of
the ChemEqui program. The best consensus models perform well both in cross-validation (root mean
squared error RMSE = 0.45-0.56 logKI2 units) and external (RMSE = 0.55) set. The models are
implemented on our website (http://infochim.u-strasbg.fr/webserv/VSEngine.html) together with the
estimation of their applicability domain and an automatic detection of potential Halogen bond
acceptors.
1. Laurence, C.; Graton, J.; Berthelot, M.; El Ghomari, M. J. Chemistry-a European Journal 2011, 17,
10431-10444
2 A. Varnek, D. Fourches, F. Hoonakker, V. P. Solov’ev J. Computer-Aided Mol. Design, 2005, 19,
693-703
3. Fiorella Ruggiu, Gilles Marcou, Alexandre Varnek and Dragos Horvath. Mol. Informatics, 2010,
29, 855 – 868
4. Fiorella Ruggiu, Vitaly Solov’ev, Gilles Marcou, Dragos Horvath, Jerome Graton, Jean-Yves Le
Questel, Alexandre Varnek Mol. Informatics, 2014, 33, 477 – 487
5. Solov’ev, V. P.; Tsivadze, A. Y. Protection of Metals and Physical Chemistry of Surfaces 2015, 51,
1-35.
15
O. Titov
D. Shulga
V. Palyulin
N. Zefirov
QUADRUPOLE-BASED CORRECTION FOR
HALOGEN BONDING DESCRIPTION IN
AUTODOCK-XB SCORING FUNCTION Chair of Medicinal Chemistry, Department of Chemistry, Lomonosov
Moscow State University, Leninskie Gory, Moscow, Russia
[email protected] For a long time halogen substitution was used in medicinal chemistry to enhance drug
properties. Halogen atoms were introduced to slow down metabolic oxidation of a compound, to
increase membrane permeability, to fill hydrophobic cavities or to participate in other nonspecific
interactions [1]. Several years ago a phenomenon of halogen bonding (XB) – an attraction between
halogen atom and a Lewis base – was discovered. This interaction pattern can be fruitfully utilized
by medicinal chemists among with the others (such as e.g. hydrogen bonding, hydrophobic
interactions, pi-pi stacking, etc.) [2]. Moreover, it is unique since it combines an electrostatic nature
and high directionality with hydrophobicity of halogen atom.
However, the rational drug design requires reliable computational approaches for XB
description at different levels of theory. Medicinal chemists widely use virtual screening and
molecular docking to cheapen and fasten hit discovery and hit-to-lead optimization. These methods
estimate affinity of a ligand with scoring functions. Despite the fact that several extra-point charge
and multipole based XB models for molecular mechanics are available, only a few XB-aware
scoring functions exists [3], which are either hardly available in software or poorly documented.
Thus a development of reliable XB-aware scoring function is still required.
Based on our previous research [4] we observe the perspectives of application of atomic
quadrupoles in scoring functions to take account of XB. The values of atomic quadrupole moments
are almost independent of chemical surroundings of halogen atom and, in contrast to extra-point
charges, are not constrained by charge conservation law, which should simplify mutual quadrupole
and charge parameterization and usage in future.
In this work, as a proof of concept, we constructed an AutoDock-XB scoring function based
on the well-established forcefield-based AutoDock function. The calibration was performed on a
set of 560 known protein-ligand halogen containing complexes. The performance of the new
scoring function was tested on a series of 5 halogenated inhibitors of phosphodiesterase type 5.
AutoDock-XB performed equally well in both scoring and docking power tests.
1. Lu Y., Wang Y. et al. Phys. Chem. Chem. Phys., 2010, 12: 4543-4551.
2. Lu Y., Liu Y. et al. Expert Opin. Drug Discov. 2012, 7: 375-383.
3. Kolár M.H., Hobza P. Chem. Rev., 2016, Article ASAP.
4. Titov O.I., Shulga D.A. et al. Mol. Inf. 2015, 34: 404-416.
This work was supported by Russian Foundation for Basic Research (Project No. 14-03-00851-a).
16
G. Marcou1,
B. Viira1,3,4
,
P. Sidorov1,2
,
D. Horvath1,
U. Maran4,
E. Davioud-Charvet3,
A. Varnek1
QSAR AND GTM STUDY OF PHENOTYPIC ANTI-
MALARIAL COMPOUNDS 1 Laboratoire de Chemoinformatique, UMR7140 CNRS-Université de
Strasbourg, France 2 Laboratory of Chemoinformatics and Molecular Modeling, Kazan
Federal University, Russia 3 UMR 7509 Centre National de la Recherche Scientifique and
University of Strasbourg, European School of Chemistry, Polymers and
Materials (ECPM), France 4 Institute of Chemistry, University of Tartu, Estonia
[email protected] This presentation concerns collaboration project of computer-aided design of antimalarial
compounds. Malaria is a parasitic tropical disease that kills around 600,000 patients every year.
Emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies
(ACTs) represents a significant public health threat, indicating the urgent need for new effective
compounds to reverse ACT resistance and cure this disease. Recently, we reported design of novel
compounds discovered with the help of QSAR modeling 1,2.
In this new project, we use a combination of QSAR and GTM 3,4 modeling in order to select potential
antimalarial agents belonging to curcuminoids family. For this, extensive curation and homogenization
of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were
conducted. As a result, a strategy was established that allowed compiling consistent training sets that
associate compound structures to the respective antimalarial activity measurements. Seventeen of
these training sets led to successful generation of classification models discriminating whether a
compound has a significant probability to be active under the specific conditions of the antimalarial
test associated to each set. In parallel, Generative Topographic Maps (GTM) of the antimalarial
activity were computed based on the same data. These models and maps were used to select the most
likely active and original compounds from series of curcuminoids. Selected compounds were
submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds
showed antimalarial activity.
1. Mourad Elhabiri, Pavel Sidorov, Elena Cesar Rodo, Gilles Marcou, Don Antoine Lanfranchi,
Elisabeth Davioud-Charvet, Dragos Horvath, and Alexandre Varnek Chemistry Eur. J, 2014, 21,
3415–3424
2. Sidorov P., Desta I. Chessé M., Horvath D., Marcou G., Varnek A., Davioud-Charvet E., Elhabiri M
ChemMedChem, 2016, accepted
3. H. Gaspar, I. Baskin, G. Marcou, D. Horvath and A. Varnek J. Chem. Inf. Model., 2015, 55 (1), 84–
94
4. P. Sidorov, H. A. Gaspar, Helena; A. Varnek, G. Marcou, D. Horvath J Comput Aided Mol Des. 2015,
29(12):1087-1108
17
V. Solov’ev1
M. Glavatskikh2,3
D. Horvath2
G. Marcou2
A. Varnek2
THERMODYNAMICS OF HYDROGEN BONDING:
FROM EXPERIMENTAL MEASUREMENTS TO
STRUCTURE-PROPERTY MODELING 1 A.N.Frumkin Institute of Physical Chemistry and Electrochemistry,
Russian Academy of Sciences, Leninskiy prosp., 31, 119071
Moscow, Russia; 2 Laboratoire de Chémoinformatique, UMR 7140 CNRS, Université
de Strasbourg, 1, rue Blaise Pascal, 67000 Strasbourg, France; 3 Laboratory of Chemoinformatics and Molecular Modeling, Butlerov
Institut of Chemistry, Kazan Federal University, Kremlevskaya 18,
Kazan, Russia;
Hydrogen bonding is of crucial importance for many properties, as well as for processes of
living and abiotic nature. For instance, it is responsible for structure formation phenomena in
biological systems and artificial self-assembling systems. A quantitative assessment of H-bond
strength has for a long time been important for the chemical community [1].
A hydrogen bond (H-bond) is formed between the molecule containing the X-H atoms,
referred as the H-bond donor (HBD), and the molecule containing the Y atom with which the H-X
forms a bond, referred as the H-bond acceptor (HBA):
X-H + Y = X-H ··· Y, X, Y = O, N, S, Se, F, etc. (1)
The stability constant logK, the Gibbs energy ΔG and the enthalpy ΔH of the 1:1
(HBD:HBA) H-bond complexation are widely used for a quantitative assessment of H-bond
strength.
In this study, we discuss results of experimental measurements of H-bond with using IR and
UV spectrophotometry, NMR spectroscopy and calorimetry for calculations of thermodynamic
quantities logK, ΔG and ΔH of hydrogen bonding in organic solution. We conclude, that known
data level makes it possible to extensive QSPR (Quantitative Structure–Property Relationships)
modeling allowing very quick and precise calculation of the strength or thermodynamic quantities
of hydrogen bonding, that would be applicable for the wide variety of the H-bond donors and
acceptors.
The estimation of the H-bond strength is based on the Gibbs energy G for the 1:1
hydrogen bond complexation (1) of different HBDs with different HBDs, which represent for up to
now the largest, structurally diversified dataset at 298 K in CCl4. The Gibbs energy for the dataset
of 3388 reactions (1) was modeled by Support Vector Machine and Multiple Linear Regression
methods using ISIDA Fragment descriptors. Successfully cross-validating models were then
challenged to make predictions for an external test set of 641 H-bond complexes. The best
consensus models perform well both in external cross-validation (root mean squared error RMSE =
1.55 - 2.35 kJ/mol) and external test set predictions with the RMSE within the range 2.17 - 5.56
kJ/mol depending on the class of Applicability Domain.
A predictor of G for hydrogen bond complexation of various organic donors with various
acceptors was created on the base of the entire training set and the best models. The SVM
consensus model is publically available on the server: http://infochim.u-
strasbg.fr/webserv/VSEngine.html.
1. Ruggiu F., Solov'ev V., Marcou G., Horvath D., Graton J., Le Questel J.-Y., Varnek A. Mol. Inf.,
2014, 33, 477–487.
VS thanks Organizers of International School-Seminar on Computer-Aided Molecular Design for
support.
18
Figure 1. Structure 14 and it's position in the thrombin binding site
1.K. Kudryavtsev, D. Shulga, V. Chupakhin, E. Sinauridze, E. Ataullakhanov, S. Vatsadze, Tetrahedron,
2014, 70, 7854-7864.
2.S.Z. Vatsadze, D. A. Shulga,Y. D. Loginova, I. A. Vatsadze, L. Wang, H. Yu, K.V. Kudryavtsev,
Mend. Comm., 2016, 26, 1-3, in press
Y. D. Loginova
S. Z. Vatsadze
D. A. Shulga
COMPUTER MODELLING OF TRISUBSTITUTED
3,7-DIAZABICYCLO[3.3.1]NONANES AS POTENT
SERINE PROTEASES INHIBITORS Department of Chemistry, M.V. Lomonosov Moscow State University,
119991 Moscow, Russia
The search for new anticoagulants is a rapidly growing area and the active researches are
carried out to identify new promising compounds. Given the tremendous growth of bioactivity
databases, the use of computational tools to predict protein targets of small molecules has been
gaining importance in recent years. In modern drug discovery, fragment-based lead discovery has
become increasingly popular as it presents a promising alternative to conventional screening
approaches. Recent work by laboratory of supramolecular chemistry and nanotechnology of organic
materials has shown the potential of using the bispidine (3,7-diazabicyclo[3.3.1]nonane) scaffolds as
inhibitors of serine proteases [1].
In recent two decades, a great amount of attention of the researchers in the field of
medicinal chemistry and organometallic derivatives is drawn to ferrocene. The aim of the work was
computer modeling of substituted 3,7-diazabicyclo[3.3.1]nonanes, including compounds with
ferrocene moiety to create potential inhibitors of serine proteases.
Steric matching of the ferrocene group to the S4 pocket caused the further development of
this idea. The main task for all targets was an effective binding with the S1 pocket. In result, energy
criteria and ligand efficiency were evaluated numerically, and steric matching and filling the pockets
were assessed visually. The presence of hydrophobic contacts, realization of the hydrogen bonds and
the formation of the alleged halogen-π-interactions at the bottom of the pocket S1 were taken into
account. For factor Xa binding energy of the whole series was between -8.4 and -10.5 kcal/mol (830
– 25 nM). For thrombin the results were even higher with the energy range between -9.8 and -11.0
kcal/mol (81 – 11 nM) with the best structure being 14. A task to have a sufficient immersion into
the S1 and S4 pockets at the same time was successfully solved for it. It also resulted in good
hydrophobic contacts in the S4 pocket, position of the halogen in the S1 pocket suggests possible
halogen-π-interaction and there is also a possible formation of two hydrogen bonds with SER195
and GLU192 (Figure 1) [2].
19
T.R. Gimadiev ,1,2
T.I. Madzhidov,1
R.I. Nougmanov,1
A. Varnek1,2
PREDICTING OF REACTIVITY FOR
BIORTHOGONAL REACTIONS OF SYDNONES
HETEROCYCLES WITH ALKYNES 1Kazan Federal (Volga Region) University, Butlerov Institute of
Organic Chemistry, ul. Kremlevskaya 18, Kazan, 420008 Russia;
2Laboratory of Chemoinformatics. University of Strasbourg. 1 rue
Blaise Pascal, 35000 Strasbourg, France;
Bioorthogonal chemical reactions, which are reactions that do not interfere with biological
processes, makes a real challenge and therefore are of major importance in the fields of chemical
biology and biochemistry. To fulfill the requirements of bioorthogonality, reaction partners must be
stable and inert towards the plethora of chemical functionalities found in living systems while
reacting selectively, efficiently and rapidly with each other under physiological conditions with no
or innocuous by-products. For the following work we investigated reaction between bicyclo-[6.1.0]-
nonyne (BCN) with sydnones.
For modeling were used 23 reactions, that appeared to be unmodelable by fragment based
QSAR. In order to solve this problem HF/6-311+G** calculations of reagents were performed in
Spartan 2014. This helped to define key factors driving the reactions (such as LUMO of sydnone,
charge on some atoms and steric effect of substituent X), but still it is not enough data points to
extract separate influence of each factor. In order to avoid this problem, DFT/PBE-3z transition state
calculations in Priroda 11 were done. This calculation’s showed fair enough correlation with
experiment R2=0.6, and RMSE in comparison with ∆G
≠ calculated from transition state theory equal
to 1.8 kcal/mol. Last model not accurate enough for exact predictions, but can be used for predicting
of bioorthoginal reactants that will give high reactivity with each other.
20
S. A. Dzhabieva
S.V. Kurbatova
PREDICTION OF BENZOTRIAZOLE DERIVATIVES
RETENTION FACTOR USING MOLECULAR
STRUCTURE DESCRIPTORS Department of Physical Chemistry and Chromatography, Chemistry
Faculty, Samara National Research University, Ac. Pavlov Str., 1,
Samara, Russia
[email protected] Quantitive structure – property relationships and its variety, such as quantitive structure –
biological activity relationships and quantitive structure – сhromatographic retention relationships
are very actual in present time. The most researchers use these approaches to determine some
properties of new unknown compounds and also its behaviour under different conditions. In this
case quantum-mechanical and quantum-chemical modeling helps to understand fundamental laws of
chemical and physico-chemical processes.
Quantum-chemical calculations were used to prediction and investigation of benzotriazole
and its some derivatives by density functional theory method using exchange-correlation functional
B3LYP and 6–31 (d) basis set. The chromatographic experiment was performed under reversed-
phase liquid chromatography (RP HPLC) on sorbents of different nature from acetonitrile-water
eluents. The results of investigations showed relationships between structural and electron
descriptors and main properties of benzotriazoles. In most cases the retention factor significantly
depends on lipophilicity, volume and polarizability of benzotriazoles molecules, especially
lipophilicity. The correlation coefficient of such equationes were in the range of 0.70-0.92. Changes
in the eluent composition considerably influence on retention, wherein the increase of acetonitrile
concentration in mobile phase decrease correlation degree between physicochemical parameters and
chromatographic retention. Retention and solvation energy correlated insignificantly because in
such calculations the nature of the sorbent is not considered. At the same time it is known, that there
is a lot of evidence of the solvates and associates formation in water - acetonitrile eluents. Thus it is
becoming a significant influence of the dipole moment on these processes. So a large value of
molecules dipole moment at close values of the other parameters reduces the retention, data given
below illustrate this fact.
V = 284.21 Å3 V = 284.33 Å
3
α = 27.85 Å3 α = 26.83 Å
3
lg P = 2.97 lg P = 3.56
µ =0.85 D µ =5.90 D
k = 3.30 k = 3.01
1. Nagy A. Physics Reports, 1998, 298(1): P. 1-79;
2. Kim H.C., Kim M.J., Lim T. et al. Thin Solid Films, 2014, 550: 421–427.
This work was supported by the Ministry of Education and Science of the Russian Federation within
the state assignment grant №4.110.2014/K.
21
N. I. Akberova1 ,
A. A. Zhmurov2 ,
T. A. Nevzorova1 ,
R. I. Litvinov3
MOLECULAR DYNAMICS OF AN ANTI-DNA
ANTIBODY FAB-FRAGMENT ASSOCIATED WITH A
DSDNA FRAGMENT 1 Chair of Biochemistry and Biotechnology, IFMB, Kazan Federal
University, Street Str. 10, Kazan, Russia; 2 Moscow Institute of Physics & Technology, 9 Institutskiy Per.,
Dolgoprudny, Moscow Region 141700, Russia; 3 University of Pennsylvania Perelman School of Medicine, 421 Curie
Blvd., Philadelphia, Pennsylvania 19104-6058, USA
nakberova@ mail.ru DNA-protein interactions, including DNA-antibody complexes, have both fundamental and
practical significance. In particular, antibodies against double-stranded DNA play an important role
in the pathogenesis of autoimmune diseases. Elucidation of structural mechanisms of an antigen
recognition and interaction of anti-DNA antibodies provides a basis for understanding the role of
DNA-containing immune complexes in human pathologies and for new treatments. Here we used
Molecular Dynamic simulations of bimolecular complexes of a segment of dsDNA with a
monoclonal anti-DNA antibody’s Fab-fragment to obtain detailed structural and physical
characteristics of the dynamic intermolecular interactions. Using a computationally modified crystal
structure of a Fab-DNA complex (PDB: 3VW3), we studied in silico equilibrium Molecular
Dynamics of the Fab-fragment associated with two homologous dsDNA fragments, containing or
not containing dimerized thymine, a product of DNA photodamage. The Fab-fragment interactions
with the thymine dimer-containing DNA was thermodynamically more stable than with the native
DNA. The amino acid residues constituting a paratope and the complementary nucleotide epitopes
for both Fab-DNA constructs were identified. Stacking and electrostatic interactions were shown to
play the main role in the antibody-dsDNA contacts, while hydrogen bonds were less significant. The
aggregate of data show that the chemically modified dsDNA (containing a covalent thymine dimer)
has a higher affinity towards the antibody and forms a stronger immune complex. These findings
provide a mechanistic insight into formation and properties of the pathogenic anti-DNA antibodies
in autoimmune diseases, such as systemic lupus erythematosus, associated with skin
photosensibilisation and DNA photodamage.
Fig.1 Results of the Principal Component Analysis (PCA) The visual representations of the
first two principal components are shown for ABDNA and ABDNA_TT on panels (a) and (b),
respectively. The first component (PC1) is the oscillatory motion around a thin part of Fab which is
marked as a ‘hinge’. The second principal components (PC2) are different in the two systems. In
ABDNA it corresponds to a motion of Fab away from the DNA molecule. In ABDNA_TT it is
represented by a shift of the portion of the heavy chain away from the binding interface. Panel (c)
shows residue fluctuations along the first PC in ABDNA (black) and ABDNA_TT (blue), the dashed
line ellipses indicate the areas of Fab’s light and heavy chains that interact with DNA. These areas
are numbered 1 through 4 and their respective positions are shown on panels (a) and (b).
This work was supported by the Program for Competitive Growth of Kazan Federal University
22
R. Ayupov1
N. Akberova1
M. Yusupov2
ANALYSIS OF MOLECULAR DYNAMICS OF SAHPF
PROTEIN 1 Department of Biochemistry and Biotechnology, Institute of
Fundamental Medicine and Biology, Kazan Federal University,
Kremlyovskaya Str., 18, Kazan, Russia 2 Laboratory of Ribosomes, IGBMC, Laurent Fries Str., 1, Illkirch
CEDEX, France
[email protected] SaHPF is protein of S.aureus (the homologue to HPF protein of E.coli) which conceivably
interacts with the 30S subunit ribosomes [1, 2] and changes its conformation so that two ribosomes
are linked together. Such interaction leads to the polypeptides synthesis shutdown, thus the cell can
safely survive in adverse environmental conditions.
Recently the attempt to define the SaHPF structure was undertaken by means of NMR. The
NMR results showed that part of protein is unstable and movable, thereby establishing the full
protein structure is quite complicated. For this reason we‘ve used bioinformatics approaches and
techniques to predict the spatial structure of SaHPF (fig.1). The protein consists of two domains and
the hinge that unites them. The first domain includes 100 amino acid residues, the hinge (with
varying degrees of packing) consists of 40 a.a. and the second domain – of 50 a.a. residues. Based
on the predicted structure of the protein we found out that the most precise NMR signals are
obtained from the first domain, the hinge and the second domain do not provide clear signals,
presumably because of their mobility.
To evaluate the degree of the protein domains and hinge mobility the molecular dynamics
method has been used. Molecular dynamics of SaHPF was performed using a Charmm force field in
the program NAMD 2.8, the simulation duration was 25 nanoseconds. The analysis of molecular
dynamics trajectories was conducted using VMD software and statistical package bio3D in the R
environment.
The analysis of RMSD (root mean square deviation from the initial structure) shows that the
protein molecule is quite movable. For simulation steps with stable and minimum RMSD values,
RMSF (deviation from average atomic coordinates value) was estimated, which showed that the
amino acid residues of the hinge and the second domain are major contributors to the mobility of
the protein. The RMSF average value for the first domain was 2.08 Å (fluctuation values for a.a.
residues were in the interval from 1.06 to 4.51 Å), for a hinge the average was 3.15 Å (from 1.14 to
5.62 Å), for second domain the average was 2.87 Å (from 1.45 to 5.11 Å). RMSF for first domain
was significantly less than the RMSF values for hinge and the second domain (p-value <0.001)
(fig.2). It is most likely that the current problems of the SaHPF structure determination by
experimental methods are caused by the mobility of the hinges and the second domain of this
protein.
Fig.1 Predicted structure of SaHPF Fig.2 95% CI of RMSF for MD frames with plato RMSD
1. Polikanov, Y. et al. Science, 2012, 336(6083): 915-918.
2. Ueta, M. et al. Genes to Cells, 2010, 15: 43-58.
The work was funded by RFBR, according to the research project No. 16-34-60001 mol_а_dk
23
V. G. Tsirelson
THE ATOMIC AND MOLECULAR INTERACTIONS:
WHAT CAN WE LEARN FROM ELECTRON
DENSITY? Quantum Chemistry Department, Mendeleev University of Chemical
Technology, Miusskaya Sq., 9, Moscow 125047, Russia
[email protected] Nowadays development of the accurate X-ray diffraction technique and quantum chemical
methods has resulted to the determination of electron density in the internuclear space of the
molecules and crystals with a typical uncertainty of ~0.05 eÅ-3. Therefore there are many attempts to
quantify the atomic and molecular interactions in terms of electron density. Respectively, many
bonding descriptors are now in use.
This talk reports on the recent developments in the search of atomic and molecular interactions
in molecules, molecular complexes and crystals and corresponding modern bonding descriptors based
on electron density and related quiatities. Important that these descriptors are equally applicable to
theoretical and experimental densities. We indicate the problems, which arise when the sprecific
interaction is identified with the bond path of QTAIMC. Also, we will demonstrate how these
developments provide new insights into the nature of atomic and molecular interactions.
Electronic internal pressure in crystalline chlorine.
This work is supported by Russian Foundation for Basic Research, grant 13-03-00767a.
24
Yu.A.Ustynyuk
HIGHLY SELECTIVE ARTIFICIAL RECEPTORS
FOR THE RECOGNITION AND BINDING OF
CATIONS AND ANIONS: COMPUTER DESIGN,
SYNTHESIS AND COORDINATION PROPERTIES. Department of Chemistry, Lomonosov Moscow State University,
Leninskie Gory, 1/3, Moscow 119991, Russia ustynyuk@nmr. chem.msu.ru
Supercomputer simulation by first-principles DFT (GGA PBE, scalar-relativistic theory,
large relativistic full-electron basis sets) was used as the efficient initial stage in the design of
arificial highly selective receptor for tetrahedral oxo-anions and for actinides and lanthanides
separation. The methods are developed for the convergent syntesis of the most promising selected
structures by anion and cationc template reactions under thermodynamic control. The phenomenon
of "anionic selection in dynamic combinatorial libraries" was discovered in the study of anionic
template effect. Large series of macrocyclic receptors on tetrahedral oxo-anions has been
synthesized, including structural analogs of phosphate and sulfate binding sites in natural phosphate
and sulfate-binding proteins, and selective receptors on perrenat- and pertechnetate-anions. New
receptors and their complexes with target ions were studied in detail by NMR, UV-vis, IR and X-ray
diffraction techniques. It has been shown that these receptors may be effectively used for the
extraction of pertehnetate anion from highly radioactive wastes arising from the reprocessing of
spent nuclear fuel and for environmental monitoring.
Based on the theoretical simulation results new polydentate N-donor heterocyclic ligands
(pyridine-2,6-dicarboxamides, 1,10-phenantroline-2,9-dicarboxamides and related compounds) were
predicted to be promising ligands with unusual and unprecedentally high selectivity for lanthanides
and actinides separation in the reprocessing of spent nuclear fuel. The synthesis of large series of
these ligands has been performed, and the results of theoretical predictions were confirmed
experimentally in extraction experiments. Selectivity factors were obtained as high as SFAm/Eu> 150
and SFAm/Cm> 7
1. Ustynyuk Yu. A. et al., Chem. Com., 2015, 51: 7466-7469.
2. Ustynyuk Yu. A. et al., Solv. Extr. Ion Exch., 2014, 32: 508–528.
3. Katayev E.A., Ustynyuk Yu.A., Sessler J.L., Coord. Chem. Rev., 2006, 250: 3004-3037.
4. Borisova N.E., Reshetova M.D., Ustynyuk Yu.A., Chem. Rev., 2007, 107: 46-79.
5. Katayev E.A., Pantos G.D., Reshetova M.D., Khrustalev V.N., Lynch V.M., Ustynyuk Yu.A.,
Sessler J.L., Angew. Chem.Int.Ed., 2005, 44: 7386-7390.
6. Sessler J.L., Katayev E., Pantos G.D., Scherbakov P., Reshetova M.D., Khrustalev V.N.,
Lynch V.M., Ustynyuk Yu.A., J. Am.Chem. Soc., 2005, 127: 11442-11446.
7. Е.А. Катаев, Д. Сесслер, Ю. А. Устынюк, Изв.РАН. сер. хим., 2009, № 9: 1729 -1742.
8. Katayev E.A., Sessler J.L., Khrustalev V.N., Ustynyuk Yu.A., J. Org.Chem., 2007, 72: 7244-
7252.
25
R. R. Nazmutdinov,
M. D. Bronshtein,
T. T. Zinkicheva,
D. V. Glukhov
MOLECULAR MODELLING OF REDOX
PROCESSES: OLD PROBLEMS AND NEW
CHALLENGES Kazan National Research Technological University, K. Marx Str., 68,
420015 Kazan, Russia
Nowadays the basic physical principles of charge transfer reactions in condensed media are
quite well understood in the framework of the classical Marcus [1] and modern quantum mechanical
theories [2-4]. Computational and quantum chemistry are, on the other hand, of crucial importance
to bridge the theory (which always plays the first fiddle) and experiment. Only with the help of
model calculations one can predict rate constants for real redox couples. Molecular modelling of
redox processes remains, however, a complicated issue so far. In this work we outline the well-
known important problems: (1) separation of quantum and classical solvent modes; (2) solvent
dynamics effects on the electron transfer (ET) kinetics; (3) extension of the Marcus model to “non-
traditional” media (e.g., room temperature ionic liquids); (4) reaction layer structure as a
“bottleneck”; (5) estimations of the electronic transmission coefficient. New challenging issues are
addressed thoroughly as well: (1) influence of orbital overlap on the activation energy of the ET
elementary act; (2) nanoscale effects. Both homogeneous and heterogeneous (i.e. proceeding at
electrochemical interfaces) reactions are considered as examples [5, 6]. It is argued that the current
computational level is not sufficient to provide quantitatively reliable data on the rate constants.
Emphasis is put, therefore, on the prediction of qualitatively interesting features of redox processes
(catalysis, inhibition, chiral recognition, nanosized electrodes and molecular junctions) which can be
compared with available experimental data. Some computational predictions prompt new
experiments in the nearest future.
1. Marcus R.A.. J. Phys. Chem. 1956, 24: 966-978 ; Ibid., 1965, 43: 679-701.
2. Kuznetsov A.M. Charge Transfer in Physics, Chemistry and Biology: the Physical Mechanism
of Elementary Processes and Introduction to the Theory, Gordon & Breach, Reading, 1995.
3. Kuznetsov A.M., Ulstrup J. Electron Transfer in Chemistry and Biology, J. Wiley & Sons Ltd.,
Chichester, 1999.
4. Schmickler W., Santos E. Interfacial Electrochemistry (2nd
Edition), Springer, Berlin, 2010.
5. Nazmutdinov R.R., Bronshtein M.D., Zinkicheva T.T., Chi Q., Zhang J., Ulstrup J. Phys. Chem.
Phys., 2012, 14: 5953-5965.
6. Nazmutdinov R.R., Bronshtein M.D., Zinkicheva T.T., Glukhov D.V. Int. J. Quant. Chem.. 2015,
116: 189-201.
This work was supported in part by the RFBR (project № 14-03-00935a).
26
I. I. Baskin1,2
DIMENSIONALITY REDUCTION IN
CHEMOINFORMATICS. GENERATIVE
TOPOGRAPHIC MAPPING 1 Chair of Polymer and Crystal Physics, Faculty of Physics,
M.V.Lomonosov Moscow State University, Leninskie Gory, Moscow,
Russia; 2 A.M. Butlerov Institute of Chemistry, Kazan Federal University,
Kremlyovskaya St. 18, Kazan, Russia;
[email protected] This presentation concerns the use of different dimensionality reduction and data
visualization techniques in chemoinformatics. It starts with the justification of the need to visualize
data as an important step to transfer the knowledge aquired by computers by analyzing raw data to
humans. We live in a three-dimensional world and have to move on a nearly flat surface of the
Earth. Our senses and our brain are adapted to work effectively under such conditions. Therefore, we
perceive information (including chemical information) better when it recalls the world we are
evolutionary adapted to interact with.
Since the world of chemical data is highly multidimensional, we need to reduce the number
of dimensions to 2 or 3 in order to take advantage of our natural biological mechanism of vision and
analysis of spatial information. Numerous methods to perform dimensionality reduction have been
developed by mathematicians for this purpose [1-3]. The approaches frequently used in
chemoinformatics are briefly discussed.
The main part of the presentation deals with the theory of the Generative Topographic
Mapping (GTM) [4] and the use of this method in the domain of chemoinformatics [5-10]. GTM is a
Bayesian approach originally developed as a probabilistic extension of Kohonen self-organizing
maps (SOMs) in order to overcome some of its drawbacks [4]. The advantages of using GTM to
process information in chemistry are explained. Several examples of mapping chemical datasets
using GTM are discussed. Recent developments discussed in the presentation concern: (i) the use of
iterative GTM and two-level meta-GTM to process big data sets [8], (ii) the concept of GTM-based
activity landscapes and their use to build QSAR/QSPR regression models and define their
applicability domains [9], (iii) different approaches to build GTM-based classification models and
define their applicability domains [6-7], (iv) Stargate GTM approach, which can be used both to
perform simultaneous predictions of several properties/activities and to detect structures with
specified activity profile (inverse-QSAR) [10].
1. Lee J.A., Verleysen M. Nonlinear Dimensionality Reduction. Springer, 2007.
2. Gorban A.N., Kégl B., Wunch D.C., Zinovyev A. (eds.) Principal Manifolds for Data
Visualization and Dimension Reduction. Springer, 2008.
3. Burges C.J.C. Foundations and Trends in Machine Learning, 2009, 2, 275-365.
4. Bishop C.M., Svensén M., Williams C.K.I. Neural Comput., 1998, 10, 215-234.
5. Maniyar D.M., Nabney I.T., Williams B.S., Sewing A. J. Chem. Inf. Model., 2006, 46, 1806-1818.
6. Kireeva N., Baskin I.I., Gaspar H.A. et al. Mol. Inf., 2012, 31, 301-312.
7. Gaspar H.A., Marcou G., Horvath D. et al. J. Chem. Inf. Model., 2013, 53, 3318-3325.
8. Gaspar H.A., Baskin I.I., Marcou G. et al. J. Chem. Inf. Model., 2015, 55, 84-94.
9. Gaspar H.A., Baskin I.I., Marcou G. et al. Mol. Inf., 2015, 34, 348-356.
10. Gaspar H.A., Baskin I.I., Marcou G. et al. J. Chem. Inf. Model., 2015, 55, 2403-2410.
27
M.Yu. Balakina
O.D. Fominykh
SELF-ASSEMBLY IN DESIGN OF QUADRATIC NONLINEAR
OPTICAL POLYMER MATERIALS Laboratory of Functional Materials, A.E. Arbuzov Institute of Organic
and Physical Chemistry KSC RAS, Arbuzov Str., 8, Kazan, Russia
Quadratic nonlinear-optical (NLO) response of polymer materials is formed due to acentrically
arranged organic chromophores introduced into polymer matrix either as guest molecules, or as a
part of the main/side chain. Self-assembly of NLO-active units exploiting the ability of
chromophores to form aggregates (both J- and H-type ones) is assumed to be a tool for the
enhancement of polymer material NLO characteristics.
Atomistic modeling of epoxy-based oligomers with multichromophore dendritic fragments in the
side chain has revealed self-assembly of azo-chromophore groups resulting in their arrangement in
stacking-like structures with the distance between the chromophore planes in the stacks ~4 Å [1].
We present here the quantum chemical study of the structure and NLO characteristics of stacking-
organized azo-chromophores. Special attention is paid to searching for the appropriate
computational scheme for the study of chromophores H-dimers; in particular, the use of various
dispersion-corrected functionals is tested when performing the calculations by DFT technique, the
set of used functionals including CAM-B3LYP, B97D, B97X-D, M06-2X. However, the effect of
H-type dimer formation on the value of first hyperpolarizability, characterizing NLO activity at the
molecular level, is found to be rather moderate as compared to that of a single chromophore, the
effect depending on the relative shift of the chromophores in the dimer. In a special case of greatly
shifted chromophores this enhancement of becomes appreciable and achieves 72%.
H-dimer
J-dimer
This moderate increase of is assumed to be caused by the violation of -conjugation along the
chromophore backbone, Raman spectra giving the evidence of this effect. Computational approach
providing the adequate simulation of experimental Raman spectra is chosen. It is shown that
conjugation in the studied azo-chromophores is essentially deteriorated by stacking dimerisation,
while formation of shifted stacked dimers strengthens conjugation.
The peculiarities of bonding in stacked dimers are characterized in the framework of Atoms in
molecules approach. Topological analysis of electron charge density distribution in stacked dimers
allows one to treat the interaction between chromophores as noncovalent van der Waals bonding [2].
The formation of J-aggregates from two and three chromophores via Hydrogen bonds is shown to
result in essential increase of first hyperpolarizability of the cluster: hyperpolarizability || of azo-
chromophores dimer is thrice greater than that of one, while for trimer it is more than six times
greater than that of one chromophore. Thus the cooperative effect of J-aggregates formation on
molecular hyperpolarizability values is revealed.
1. Fominykh O.D., Balakina M.Yu. Macromol. Symp., 2012, 316: 52-62.
2. Fominykh O.D., Sharipova A.V., Balakina M.Yu. Int.J.Quant.Chem., 2016, 116: 103-112.
Partial financial support of RFBR (project № 15-03-04423а) is gratefully acknowledged.
28
K. Klimenko 1,2
,
G. Marcou1,
D. Horvath1,
A.Varnek1
CHEMICAL SPACE MAPPING AND
STRUCTURE-ACTIVITY ANALYSIS OF THE
ChEMBL ANTIVIRAL COMPOUND SET. 1 Laboratoire de Chemoinformatique, UMR 7140
CNRS/Université de Strasbourg, 1, rue Blaise Pascal, Strasbourg
67000, France, 2 Department on molecular structure and chemoinformatics, A.V.
Bogatsky Physico-Chemical Institute of NAS of Ukraine,
Lyustdorfskaya doroga, 86, Odessa 65080, Ukraine
[email protected] Curation, standardization and data fusion of the antiviral information present in the ChEMBL public
database led to the definition of a robust data set, providing an association of antiviral compounds to
seven broadly defined antiviral activity classes. Generative Topographic Mapping (GTM) subjected to
evolutionary tuning, was then used to produce maps of the antiviral chemical space, providing an
optimal separation of compound families associated with the different antiviral classes. The ability to
pinpoint the specific spots occupied (responsibility patterns) on a map by various classes of antiviral
compounds opened the way for a GTM-supported search for privileged structural motifs, typical for
each antiviral class. The privileged locations of antiviral classes were analyzed in order to highlight
underlying privileged common structural motifs. Unlike in classical medicinal chemistry, where
privileged structures are, almost always, predefined scaffolds, privileged structural motif detection
based on GTM responsibility patterns has the decisive advantage of being able to automatically capture
the nature (“resolution detail” – scaffold, detailed substructure, pharmacophore pattern, etc.) of the
relevant structural motifs. Responsibility patterns were found to represent underlying structural motifs
of various natures – from very fuzzy (groups of various “interchangeable” similar scaffolds), to the
classical scenario in medicinal chemistry (underlying motif actually being the scaffold), to very
precisely defined motifs (specifically substituted scaffolds).
29
V. Torbeev UNDERSTANDING PROTEIN FUNCTION BY
TOTAL CHEMICAL SYNTHESIS 1 Institute de Science et d'Ingénierie Supramoléculaires, UMR 7006,
Université de Strasbourg, 8 allée Gaspard Monge, 67000 Strasbourg,
France
[email protected] Total synthesis of proteins via methods of organic chemistry evolved as a powerful
methodology for addressing problems of chemical biology [1]. It allows preparation of natural proteins
and protein constructs bearing unlimited combination of post-translational modifications, labels and/or
unnatural amino acids, which cannot be prepared by other means. Therefore, structure-function,
biophysical, biological and bioinformatic studies can be performed in unprecedented ways. Modern
methods allow total synthesis of proteins up to ~200-300 amino acid residues long [2,3], which
exceeds the typical size (~150 amino acids) of a protein domain.
As an example, the application of chemical strategies will be illustrated for studying the role of
conformational protein dynamics in the mechanism of HIV-1 protease catalysis [4,5]. More than 30
chemical analogs were prepared for this important enzyme including protein variants where key
residues were replaced by unnatural substituents with inverted stereocenters (such as D-amino acids,
allo-isoleucine), stereochemically constrained residues such as α,α’-substituted amino acid or
backbone-modified building blocks such as α-hydroxy carboxylic acids. In addition, nitroxide spin-
and ½-nuclei spin-labels were introduced site-specifically for EPR and NMR spectroscopies,
respectively. Steady-state enzyme kinetics, X-ray structures and various other biophysical
measurements (NMR relaxation, pulse-EPR methods, molecular dynamics simulations) were
performed. Obtained data led to the conclusion that the role of conformational dynamics is critical in
the catalytic mechanism of this enzyme, moreover, the major ‘conformational contribution’ to catalytic
rate is preorganization of the active site [5].
Other data that will be highlighted in the lecture include: (i) an application of chemical protein
synthesis for mechanistic studies of protein misfolding and aggregation into amyloids, including chiral
recognition phenomena in amyloid growth [6,7]; and (ii) a novel strategy for structure-function studies
of intrinsically-disordered proteins.
1. 1. Kent S. B. H. Chem. Soc. Rev., 2009, 38: 338-351.
2. Torbeev V., Kent S. B. H. Angew. Chem. Int. Ed., 2007, 46: 1667-1670.
3. Weinstock M. T. et al. Proc. Natl. Acad. Sci. USA, 2014, 111: 11679-11684.
4. Torbeev, V. et al. J. Am. Chem. Soc., 2009, 131: 884-885.
5. Torbeev, V. et al. Proc. Natl. Acad. Sci. USA, 2011, 108: 20982-20987.
6. Torbeev, V. et al. J. Am. Chem. Soc., 2015, 137: 2524-2535.
30
T.I. Madzhidov,1
T.R. Gimadiev,1,2
R.I. Nugmanov,1
I.I. Baskin,3
I.S. Antipin,1
A. Varnek 1,2
PREDICTION OF TAUTOMERIC EQUILIBRIA: QSAR
VS QUANTUM CHEMISTRY 1
Laboratory of Chemoinformatics and Molecular Modelling, A.M.Butlerov
Institute of Chemistry, Kazan Federal University, Kremlyovskaya St. 18,
Kazan, Russia; 2 Laboratoire de Chemoinformatique, UMR 7140 CNRS/Université de
Strasbourg, 1, rue Blaise Pascal, Strasbourg 67000, France;
3 Chair of Polymer and Crystal Physics, Faculty of Physics,
M.V.Lomonosov Moscow State University, Leninskie Gory, Moscow,
Russia
Chemical reactivity, spectral and physico-chemical properties of compounds are highly dependent
on equilibrium between different tautomeric forms, but usually the form that is the most stable in water is
considered in chemical databases or QSAR/QSPR modeling. Since many experiments are carried out in
non-aqueous media or water-organic solvent mixtures, prediction of the tautomers’ population as a
function of solvent represents a real challenge.
In this work, we report QSPR modeling of tautomer equilibrium constants (logKT) in different
solvents and water-organic solvent mixtures. Two types of external test were selected for examination of
produced model and comparison with other methods. Each reaction was encoded by Condensed Graph of
Reaction (CGR) [1], that were used for ISIDA fragment descriptors generation [1]. Solvents were
encoded by 15 descriptors representing solvent polarity, polarizability, H-acidity, basicity and
temperature [2]. QSPR models were built using SVM method with parameters optimized by genetic
algorithm. They have reasonable predictive performance: consensus RMSE was about 0.65 logKT units in
30 x 5-fold cross validation for universal models and 0.34-0.97 for specific models. RMSE of tautomer
form distribution prediction on the universal model is about 17% (for consensus model predictions for
test sets during cross-validation). The dominant tautomer was predicted correctly in 84% of cases. Test1
was predicted with RMSE 1.63, Test2 - with RMSE 0.73.
For comparison, logKT in several pure solvents were also assessed by quantum chemical (QC)
calculations. For both external validation sets DFT B3LYP/6-311++G(d,p) with continuum solvation
model was applied. RMSE of prediction for Test1 and Test2 was 5.8 and 1.62 with CPS 48% and 74%
respectively. So, developed QSPR models perform better than QC calculations on given basis set.
1. 1 Varnek, A.; Fourches, D.; Hoonakker, F.; Solov’ev, V. P. J Comput Aided Mol Des 2005, 19,
693.
2. T. I. Madzhidov, P. G. Polishchuk, R. I. Nugmanov, A. V. Bodrov, A. I. Lin, I. I. Baskin,A.A.
Varnek, I. S. Antipin. Russian Journal of Organic Chemistry, 2014, 50 (4), 459-463.
31
T. Salah1
S. Belaidi1
N. Melkemi1
I. Daoud2
CONCEPTUAL DFT AND MOLECULAR DOCKING
COMBINATION FOR UNDERSTANDING LIGAND-
RECEPTOR BINDING MODE 1 Group of computational and pharmaceutical chemistry, LMCE
laboratory, university of biskra, 07000 – biskra - algeria; 2 laboratory of naturals products and bio actives-lasnabio , department
of chemistry, aboubakr belkaid university, 13000 - tlemcen – algeria;
Current knowledge about chagas disease, the potentially life-threatening illness, caused by
the protozoan parasite (T.Cruzi), has led to the development of new drugs and the understanding of
their mode of action [1,2].
Chemists face a bewildering amount and diversity of data in their quest to discover the
physical and chemical properties of substances. Therefore, conceptual density functional theory
offered a perspective for the interpretation/prediction of experimental/theoretical reactivity data
[3,4], although, enhanced reactivity can be affected by steric hindrance effects, which is not
encapsulated in the definition of the reactivity indicators, for this reason, we propose the
combination of conceptual DFT and Molecular Docking axes for understanding the electronic and
steric behaviors of receptor-binding mode of trypanocidal compounds to guide design and achieving
a parasitological cure against trypanosoma cruzi. [5].
All the obtained results from conceptual DFT, Molecular Docking and literature experiments
were found to be in accordance. This, improve the affinity of this investigation in understanding
Trypanosoma cruzain inhibition.
1. Salah, T. et al. Comput. Theor. Nanosci. 2015, 12, 2421-2427.
2. Salah, T. et al. Rev. Theor. Sci. 2015, 3, 355-364.
3. Geerlings, P. et al. Chem. Rev. 2003, 103, 1793-1873.
4. Geerlings, P. et al. Phys. Chem. Chem. Phys. 2008, 10, 3028-3042.
5. Trott, O. et al. J. Comput. Chem. 2010, 30, 455-461.
32
S.Shermukhamedov,
V. Glukhov,
R. Nazmutdinov
DOES NICKEL SEGREGATION OCCUR IN
BIMETALLIC NICU NANOPARTICLES?
Kazan National Research Technological University, 420015 Kazan,
Russian Federation
[email protected] Bimetallic (in particular, NiCu) nanoparticles (NP) are frequently used as catalysts in fuel
cells; that is why a molecular level knowledge about their surface structure is crucial for
understanding the elementary act of chemical processes. Segregation phenomena in NiCu alloys
were intensively studied using various experimental technique (Auger-electron and ultra-violet
photoemission spectroscopy, low energy ion scattering, field-ion microscopy and time-of-flight
atom probe technique) [1-6]. Only a few attempts were made so far to describe the structure of
NiCu nanoparticles with the help of Monte Carlo (MC) and molecular dynamics (MD) methods [7,
8], or on the basis of experimental studies and MC simulations [9]. The segregation of nickel atoms
remains, however, a controversial and challenging issue both for the alloys and for the nanoparticles.
In this work we employ atomistic MC simulations (NVT ensemble) in order to gain a deeper insight
into this problem considering NiCu NPs of different size in a wide range of their composition.
Atomic interactions are described by a set of pair Morse potentials, as well as using the Embedded
Atom Method.
According to our results the structure of model nanoparticles is close to “core-shell” type.
The nickel segregation is argued to be noticeably weaker as compared with copper. The Ni atoms
prefer to segregate at the second surface layer of the nanoparticles (when the copper fraction
prevails). For the NP diameters ranged from 0.5 to 10 nm no significant differences in segregation
features are observed.
1. H.H. Brongersma, T.M. Buck, Surf. Sci. 53 (1975) 649-658.
2. K. Watanabe, M. Hashiba, T. Yamashina, Surf. Sci. 61 (1976) 483-490.
3. Y.S. Ng, T.T. Tsong, S.B. McLane, Jr. Phys. Rev. Lett. 42 (1979) 588.
4. D.T. Ling, J.N. Miller, I. Lindau, W.E. Spicer, P.M. Stefan. Surf. Sci. 74 (1978) 612-620.
5. T. Sakurai, T. Hashizume, A. Jimbo, A. Sakai, S. Hyodo, Y. Kuck, H.W. Pickering. Phys. Rev.
B, 34 (1986) 8379-8390.
6. T. Sakurai, T. Hashizume, A. Kobayashi, A. Sakai, S. Hyodo, Phys. Rev. Lett, 55 (1985) 514-
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7. D.S. Mainardi, P.B. Balbuena. Langmuir, 17 (2001) 2047.
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9. A.G.Oshchepkov, P.A.Simonov, O.V.Cherstiouk, R.R.Nazmutdinov, D.V.Glukhov,
V.I.Zaikovskii, T.Yu.Kardash, R.I.Kvon, A.Bonnefont, A.N.Simonov, V.N.Parmon,
E.R.Savinova. Top. Catal. 58 (2015) 1181-1192
Fruitful discussions wirh Paola Quaino and Elena Savinova are greatly appreciated. This work was
supported in part by the RFBR (project № 14-03-00935a).
33
A. S. Loginova1
S. K. Ignatov1
L. V. Moskaleva2
M. Bäumer2
THE REACTIVITY OF –O–AU–O– CHAIN
STRUCTURES ON THE MODEL AU(321) SURFACE:
A COMPUTATIONAL STUDY 1 Department of Chemistry, N.I. Lobachevsky State University of
Nizhny Novgorod, Nizhny Novgorod, 603950, Russia; 2 Institute of Applied and Physical Chemistry and Center for
Environmental Research and Sustainable Technology, Universität
Bremen, Bremen, 28359, Germany;
[email protected] In contrast to bulk gold, nanostructured forms of gold recently emerged as remarkably active and
selective catalysts, especially in oxidation reactions at low temperature.1,2
Silver and gold have
similar atomic radius and can form continuous solid solutions for all compositions. because of
Catalytic properties of Au-Ag alloy nanocatalysts can be tuned by varying the concentration of Ag,
which should enhance predisposition to bind and activate molecular oxygen.3
Several recent studies
reported high catalytic activity of Au-Ag nanoparticles for alkene epoxidation, 4
low-temperature CO
oxidation5,6
, and other reactions, in many cases exceeding that of monometallic Au or Ag catalysts.
In order to understand the synergistic effect of gold and silver components in a bimetallic catalytic
system, the knowledge of oxidation properties of Au-Ag bimetallic surfaces is important. In this
work we study theoretically the relative thermodynamic stability of various forms of adsorbed
oxygen on alloyed surfaces as a function of temperature and O2 partial pressure by means of density
functional theory and “ab initio thermodynamics”.7
We identify (–Au–O–) chain structures as especially energetically favorable forms of adsorbed
oxygen on gold-rich surfaces even at relatively low O coverage. We address the reactivity of these
chains with CO and we show that –O–Au–O– linear fragments can form as a result of O2
dissociation on the surface with pre-adsorbed O, significantly lowering the dissociation barrier of
O2.
We used the model stepped and kinked Au(321) surface. To model alloyed surfaces, we
replaced some of the Au atoms in the top layer with Ag. The DFT calculations were carried out with
a plane-wave based method using the gradient-corrected PBE exchange-correlation functional.8
The
unit cell contains 28 atoms of gold and 4 oxygen atoms.The relative stability of the two different
types of chain structures has been studied under the coordination of CO on the surface of the Au
(321).
We studied two ways of the attack CO on the surface: (1) when CO is located directly on the
chain –O-Au-O-; (2) when CO is localized near to the chain. These chains can be reacted with co-
adsorption of CO by multistage reaction with an activation barrier limiting step. Energy transition
states of reactants is below, so we can assume that the reaction proceeds easily.
1. M. Haruta, T. Kobayashi, H. Sano, N. Yamada, Chem. Lett. 16 (1987) 405–408.
2. M.D. Hughes, Y.-J. Xu, P. Jenkins, P. McMorn, P. Landon, D.I. Enache, A.F. Carley, G.A.
Attard, G.J. Hutchings, F. King, E.H. Stitt, P. Johnston, K. Griffin, C.J. Kiely, Nature 437 (2005)
1132–1135.
3. L.V. Moskaleva, S. Röhe, A. Wittstock, V. Zielasek, T. Klüner, K.M. Neyman, M. Bäumer, Phys.
Chem. Chem. Phys. 13 (2011) 4529.
4. D.I. Kondarides, X.E.Verykios, Stud. Surf. Sci. Catal. (1994) 82, 471-480.
5. Y. Iizuka, A. Kawamoto, K. Akita, M. Daté, S. Tsubota, M. Okumura, M. Haruta, Catal. Lett. 97
(2004) 203-208.
6. J.-H. Liu, A.-Q. Wang, Y.-S. Chi, H.-P. Lin, C.-Y. Mou, J. Phys. Chem. B 109 (2005) 40-43.
7. K. Reuter, M. Scheffler, Phys. Rev. B 65 (2001) 035406.
8. L.V. Moskaleva, T. Weiss, T. Klüner, V. Zielasek, T. Klüner, M. Bäumer, J. Phys. Chem. C 119
(2015) 9215-9226.
This work was supported by the RFBR (Project No. 14-03-00585)
34
N.A. Burmistrova1,
I. Vakulin2
AROMATIC AMINE IN DESIGN OF FLUORESCENT
PROBE BASED ON PHOTOINDUCED ELECTRON
TRANSFER 1
Department of General and Inorganic Chemistry, Institute of
Chemistry, National Research Saratov State University, Astrakhanskaya
Str., 83, Saratov, Russia; 2
Faculty of Chemistry, Bashkir State University, Validy Str., 32, Ufa,
Russia
Fluorescent probe based on photoinduced electron transfer (PET) is the example of
sucsessful applying of molecular modeling methods in analytical chemistry [1]. Combination of
highly sensitive fluorimetry, fast PET process and reversiblу redox reactions have some benefits in
the development of sensory systems. The typical structure of an intramolecular PET system includes
an electron donor (receptor) and an electron acceptor (fluorophore) which are linked together by a
flexible chain. Mostly PET probes desined as "OFF-ON" fluorophores. In this case the electron
transfer from the HOMO of the receptor in reduced state to the partially occupied HOMO of the
photoexcited acceptor may quench the fluorescence from the fluorophore. If receptor is oxidazes by
analyt, the PET is interrupted and fluorescence of fluoriphore is observed. The behavior of PET
fluorescent probes is described on the basis of the analysis of the energies of the frontier molecular
orbitals. Despite the fact that PET fluorescent probes are widespread in biochemistry, the benefits of
using aromatic amine as donor moity are not fully used and limited to probes based on a probe on
the basis of 1,8-naphthalimide and anisidine (HP Green) [2]. Recently the theoretical investigation
by density functional theory calculations of structural analogs of HP Green was presented [3] and
results has shown that appearance or disappearance of the PET can be predicted by the energy
difference between the frontier orbitals and the nature of their location of donor and acceptor
moieties, which is in agreement with the PET theory and observed experimental data.
We focused our efforts on the theoretical study of the the behavior of the fluorescent probe
on the basis of 1,8-naphthalimide and para-derivatives of aniline as well as N-methylaniline and
diphenylamine. The calculations arylamine, their protonated state and cation-radicals were
performed in the software package FireFly 8.0. A search of the equilibrium geometry was carried
out using the split-valence basis set 6-31G(d, p), taking into account the electron correlation on the
density functional theory hybrid functional B3LYP. Analytical vibrational frequency computations
at the optimized structure were then performed to confirm that the optimized structure was at an
energy minimum. Visualization of the structures and HOMO and LUMO molecular orbitals was
performed with ChemCraft (1.7).
The effect of electronic structure of donor moiety and conformational characteristics of the
N-substituted aniline derivative molecules on the PET efficiency are discussed. The quantitative
relationships between molecular descriptors and donor moiety properties can be useful to improve
the efficiency of PET fluorescence probe for this series of compounds.
1. De Silva A.P. et al. Analyst, 2009, 134: 2385-2393.
2. Burmistrova N.A. et al. Sensors and Actuators B. Chemical. 2014, 193: 799-805.
3. Burmistrova N.A. et al. Proc. SPIE. SFM 2014: Optical Technologies in Biophysics and Medicine
XVI; Laser Physics and Photonics XVI; and Computational Biophysics. 2015, 9448: 94480R.
The work was supported by the Russian Scientific foundation (project 14-13-00229).
35
N.A. Nekrasova1,2
S.V. Kurbatova1
QUANTUM CHEMISTRY APPROACH TO STUDYING
OF TETRAHYDROQUINOLINES ADSORPTION
UNDER LIQUID CHROMATOGRAPHY CONDITIONS 1 Department of Physical Chemistry, Chemical Faculty, Samara
National Research University, Ac. Pavlov Str., 1, Samara, Russia; 2 Samara Center for Theoretical Materials Science, Ac. Pavlov Str., 1,
Samara, Russia
[email protected] The problem of determination of quantitative relations between molecular structure of
compounds and different macroscopic quantities, including chromatographic retention, remains
relevant. There are different approaches to solving it, which are based on combined using of
structural descriptors and parameters of the studying system [1]. Quantum chemical methods allow
one to calculate molecular characteristics, responsible for intermolecular interactions in the sorption
process. Saturated heterocycles were chosen as research objects, as they are the structural basis for
many important substances and, at the same time, their chromatographic behavior remains almost
unexplored. In this connection, the purpose of our study was to investigate influence of the
electronic, physicochemical and structural parameters of tetrahydroquinoline derivatives on their
chromatographic retention under reverse-phase liquid chromatography conditions.
Chromatographic experiment was performed using water-acetonitrile solutions (40 – 90%
acetonitrile) as a mobile phase and porous graphitized carbon as a stationary phase at the room
temperature. Physicochemical parameters of sorbates were calculated in the Gaussian 09 package by
DFT / B3LYP / 6-31G (d,p) method; the solvent effects were taken into account by the PCM-model
(Polarizable Continuum Model).
It was found that among the calculated parameters polarizability, lipophilicity, surface area
and area of projection of the molecules on plane are in the best agreement with retention of
tetrahydroquinoline derivatives. The increasing of these parameters leads to linear increasing of
retention factors due to the strengthening of sorbates dispersion attraction to the sorbent. The dipole
moment growth is accompanied by increasing of induction interactions with graphite π-electron
system and retention increasing. Among others, we received six two-parameter equations with
correlation coefficients above 95%, and their prognostic applicability was shown. The solvation
energy of compounds in the eluent solution has ambiguous effect on retention, but its combination
with another parameters significantly improves the predictive ability of the obtained equations. The
main feature of investigated compounds is their non-planarity, therefore they can differently
orientate in the sorbent surface. Thus, chromatographic complexes formed in the sorption process
were modeled and optimized, the preferred orientation of molecules with respect to the sorbent
surface was revealed and adsorption and solvation energies of the complexes were calculated. It was
shown that sorbates with carboxyl, hydrazide and ester groups arrange by carbonyl oxygen to the
bulk phase of the solution. Linear correlation between the retention factor and the adsorption energy
of the most of sorbates was observed. Generally, the obtained correlations allow one to predict the
adsorption behavior of structurally similar compounds under conditions of reversed phase liquid
chromatography.
1. Kaliszan R. Chem. Rev., 2007, 107: 3212 - 3246.
The work was supported by the Russian Government (grant № 14.B25.31.0005).
36
M. K. Glagolev1
A. A. Lazutin1
V. V. Vasilevskaya1
MULTI-SCALE SIMULATION OF
HYPERCROSSLINKED POLYSTYRENE NETWORKS 1 Laboratory of Physical Chemistry of Polymers, A. N. Nesmeyanov
Institute of Organoelement Compounds of RAS, Vavilova st., 28,
Moscow, Russia
[email protected] A multi-scale molecular dynamics simulation was used to study formation of
hypercrosslinked polystyrene networks [1-3]. The networks were formed by simulated crosslinking
of linear polystyrene dissolved at different concentration in dichloroethane by monochlorodimethyl
ether. The simulated synthesis was performed at different rates and with varying final degrees of
cross-linking. The multi-scale algorithm involved atomistic molecular dynamic simulations with
mapping and reverse mapping procedure and comprised the following consecutive stages: molecular
dynamics atomistic simulation of a polystyrene solution, mapping of atomistic structure onto coarse-
grained model, formation of cross-links, reverse mapping and relaxation of the restored atomistic
structure dissolved in dichloroethane and in dry state. The rate of cross-linking reaction was
controlled by variation of the probability of chemical bonding between the particles within the
reaction distance on individual step of the simulation [3].
The values of the elastic modulus obtained from the restored atomistic configurations were in
reasonable quantitative correspondence with experimental data. In coarse-grained representation
dependence of mechanical properties on polystyrene concentration and degree of cross-linking were
reflected qualitatively [2]. Both atomistic and coarse-grained approaches supply close values of
specific surface and pore size distributions. It was shown that the rate of cross-linking influences the
structure of "synthesized" hypercrosslinked networks: slowly cross-linked polymer networks have
smaller total specific surface, lower average density, larger pores than those cross-linked at high rate
[3].
(a) (b) (c)
Figure 1. Cross-linking of linear polystyrene by monochlorodimethyl ether (a); snapshots of dry
hypercrosslinked polystyrene networks (cross-linking degree 200%): slowly cross-linked (b) and fast
cross-linked (c).
1. A. A. Lazutin, M. K. Glagolev, V. V. Vasilevskaya and A. R. Khokhlov. Hypercrosslinked
polystyrene networks: An atomistic molecular dynamics simulation combined with a
mapping/reverse mapping procedure. J. Chem. Phys., 2014, Vol. 140, 134903
2. M. K. Glagolev, А. А. Lazutin, V. V. Vasilevskaya. Macroscopic properties of hypercrosslinked
polystyrene networks: an atomistic and coarse-grained molecular dynamics simulation.
Macromolecular Symposia, 2015, vol. 348, p. 14-24, DOI: 10.1002/masy.201400148
3. M. K. Glagolev, A. A. Lazutin, V. V. Vasilevskaya, A. R. Khokhlov. Influence of cross-linking
rate on the structure of hypercrosslinked networks: Multiscale computer simulation. Polymer, 2016,
86, 168-175.
The work was supported by RFBR project 14-03-00073
37
R.I. Nugmanov1
T.I. Madzhidov1
A. Varnek1,2
AUTOMATIC REACTION PROCESSING AND
STANDARDIZATION WORKFLOW 1Kazan Federal (Volga Region) University, Butlerov Institute of
Organic Chemistry, ul. Kremlevskaya 18, Kazan, 420008 Russia;
2Laboratory of Chemoinformatics. University of Strasbourg. 1 rue
Blaise Pascal, 35000 Strasbourg, France;
A priori assessment of optimal reaction conditions for a given transformation is the holy grail of
synthetic organic chemistry. Usually, the choice of reaction conditions proceeds in essentially
empirical way: the chemist relies either on his/her own experience or on information for similar
reactions retrieved from the literature. However, the exponential growth of current chemical
information makes the task of analysis and generalization extremely difficult for the human mind
alone and requires special approaches and tools in order to efficiently extract such knowledge from
raw data. Both automatic knowledge extraction and information retrieval suffer from the only one
problem: despite a very large amount of reaction data exist in the literature that are manually
collected by such database vendors like Reaxys (60 mln reactions in database) and CAS (100 mln
reactions in database) quality of extracted data in database is not satisfactory.
The problem could be caused not only by errors in the structure extraction but also by intrinsic
features of chemical compounds like tautomerisation, epimerisation, racemization and others. These
problems are usually solved by means of structure standardization and automatic or manual data
curation procedures.
However for databases of chemical reactions there are problems that never appeared for chemical
substances additionally to regular structure standardization issues.
We present a prototype of the system for reaction standardization. It consists from different
modules responsible for special steps or reaction cleaning. For the time being it could not resolve all
mentioned problems but already allows solving the most common ones: atom-to-atom mapping
errors by using CGR approach1, unbalanced reactions, salts and tautomerisation.
1. Hoonakker, F., Lachiche, N. & Varnek, A. Condensed Graph of Reaction: considering a
chemical reaction as one single pseudo molecule. Int. J. Artif. Intell. Tools 20, 253–270
(2011).
The research was supported by Russian Scientific Foundation, grant 14-43-00024. We thank the Reaxys
database (Elsevier, Netherlands) for providing us with the experimental reaction data and ChemAxon
company for the software license.
38
F.T. Adilova 1
A.A. Ikramov 2
EVALUATION OF THE MODELABILITY OF
COMPOUNDS SET IN QSAR 1 Laboratory of Bioinformatics, Institute of Mathematics, National
University of Uzbekistan; 2 Faculty of Mechanics and Mathematics, National University of
Uzbekistan; [email protected]
Extensive research shows that it is often impossible to build QSAR models with good
predictive power, even when using the most sophisticated algorithms and meticulous simulation.
So it was proposed to use an a priori estimate the feasibility of forecasting QSAR models for a
specific set of bioactive compounds. The presence in the sample “activity cliffs”, - pairs or groups
of structurally similar or analogous active compounds having a large difference in potency, it is of
great difficulty for QSAR modeling. Therefore, SALI, and ISAC indexes have been developed to
detect activity cliffs.
A generalization of these indexes is the index of "Model-ability" (MODelabIlity, – MODI)
as a quantitative measure of a quick assessment of whether you can get the model (s) forecast for a
given set of chemical data. Efficiency of QSAR predictive models, denoted QSAR_CCR,
expressed in terms of classification accuracy assessment. We used two algorithms,- SVM, and
Random Forest (RF) in order to get answers to the following two questions: (1) whether the
classification accuracy depends on the algorithms, the size of the sample, and set of descriptors?
(2) whether the accounting "model-capacity» (MODI) of original sample improved the predictive
efficiency of QSAR models?
Computational experiments produced the answer to the first question:
- SVM results shown at slightly higher (8.1%). At the same time the RF gave 4 times more
correct answers (32.1%). It should be noted that the best results were obtained on a sample of a
minimum (1000 compounds) size;
-use of two types of descriptors let’s say a lack of significance of this choice.
The answer to the second question obtained as a result of computing experiments, which
consisted of: (1) computation of MODI on a sample of 2,000 objects; (2) the selection of a "model-
able" sample, and (3) the classification. 2000 compounds were selected, describing by 23
descriptors in which MODI coefficient = 0.55 was calculated. Next it was launched RF and SVM:
an average of the two methods added to 10% the right decision.
It was further verified the statement from [1] about getting adequate QSAR models in the
case of values MODI> 0.8. From 9666 chemical compounds selected a subset of the 2,000
compounds, with a value of MODI = 0.92. Classification results on both algorithms were low: for
RF, - 35,5% at best, and for SVM, - 23,7%. On the other sample with MODI = 0.57 obtained
results for the RF, - 28,5%, and for the SVM, - 21,9%.
Thus, we received the answer to the second question: MODI of the original sample is not
provides the improvement in the efficiency of the predictive ability of QSAR models.
Therefore, we compared the efficacy of two of the most used in cheminformatics
classification algorithms in solving the problem of the original sample model-capacity ratings for
QSAR - modeling as the criteria for their success in the development of optimal models. In contrast
to the generally accepted in this sense the acceptability index model-capacity MODI we have seen
that in some cases, this index is a poor reflection of the ability of the sample to be successfully
used to build the model forecast "structure-activity".
1. Alexander Golbraikh, Eugene Muratov, Denis Fourches, Alexander Tropsha Data Set
Modelability by QSAR. J. Chem. Inf. Model. 2014, 54, 1-4
39
F.T Adilova,
R.R. Davronov,
U.U.Jamilov,
Sh.N. Murodov
PREDICTION OF LD50 ACTIVITY OF
ORDINARY HARMALA ALKALOIDS OF
QUINAZOLINE QUINOLONE STRUCTURE AND
THEIR DERIVATIVES BASED ON QSAR MODELS Institute of mathematics, National University of Uzbekistan
The aim of this work is to model the relationship between the biological activity and
hydrophobicity of chemicals based on QSAR. Performance criteria of developed models are their
adequacy (in a statistical sense) and interpretability. This paper analyzes several types of models and
different sets of descriptors in solving a concrete task of forecast of LD50 activity of ordinary harmala
alkaloids quinazoline quinazolone structure and their derivatives.
Two types of models 'hydrophobicity - activity "particularly, parabolic and bilinear will be investigated
in spaces of different descriptors: physico-chemical (logP, εlumo, εhomo), a combination of physico-
chemical and topological descriptors (Balaban, Randič Wiener indexes and polarity).
According to modern chemical nomenclature the alkaloids of harmala ordinary quinazoline
structure and derivatives investigated in [1] are divided into two groups: 1) the compounds with the
structure of a quinolone structure or deoxypeganine series (compounds 1 to 43); and 2) compound of
quinazolin structure (compounds 46 to 65).
In according with standard procedure of regression analysis, each of these groups divides into a
training and test set. As the statistical criteria of the models adequacy used: the coefficient of
determination R2, Fisher test, the value of the confidence interval at the p ≤0.01 (training set).
In the first series of computational experiments (CE_1) on training samples of the above two groups of
compounds were constructed parabolic and the bilinear model using physico-chemical descriptors logP,
εLUMO, εHOMO.
In the second series of computational experiments (CE_2) on training samples of the compounds
of the first and second groups, was designed a parabolic bilinear model ,based on combined the physic-
chemical and topological descriptors (Balaban, Randič, Wiener indexes and polarity).
From a comparison of CE_1 and CE_2 results, the following conclusions can be done:
1. The bilinear model is superior to the accuracy of the parabolic model in both series of
experiments;
2. A combination of physic-chemical and topological descriptor improves the accuracy of the
models;
3. Models constructed on the data of the second group of compounds in both experiments have
higher accuracy than models based on the data of the first group of compounds.
The aim of the third series of computational experiment (CE_3) was to check the last inference
in the combined space of descriptors. On training samples were constructed linear and non-linear
(quadratic) regression model using MATLAB with automatic selection of descriptors.
The trend in the difference between the models of the first and second group of compounds became
even clearer that leads to the assumption that there is a difference in the structure of the original data;
namely, we can assume that the data of the second group of compounds are more homogeneous.
Conclusion
Thus, this study demonstrated the feasibility of using computer simulation QSAR models of
different types. From the analysis of the results of numerical experiments one can conclude that in each
case it is necessary to have several models from the comparison of the accuracy of which selected the
optimal model. Predicting is performed on the optimal model under the control of the statistical
characteristics of the sample (emissions, omissions, noise), which will provide reliable prediction of
activity of the compound based on its structure.
_____________________________________________________________________________
1. Тulyaganov N. Pharmacological studies of LD50 activity of alkaloids of harmala ordinary with
quinazoline quinazolone structure and their derivatives The abstract of doctoral dissertation
,Moscow,1981
40
I. Fedorova
AB INITIO STUDIES OF H-BONDING AND PROTON
TRANSFER IN COMPLEXES OF PHOSPHORIC ACID
WITH DMF AND DMSO G. A. Krestov Institute of Solution Chemistry of Russian Academy of
Sciences, Street Akademicheskaya 1, Ivanovo, Russia;
In this work, the results of quantum-chemical investigations of H-bonding and proton
transfer process in various complexes of phosphoric acid (H3PO4) with dimethylsulfoxide (DMSO)
and N,N-dimethylformamide (DMF) have been demonstrated. These model systems represent a first
step towards the more detailed understanding of the proton conduction mechanisms in realistic
phosphoric acid based polymer electrolyte materials. We have considered following type of
complexes: (H3PO4)n–base and H3PO4–(base)m for n=1, 2 and m=2, 3 (where base is DMF and
DMSO). The data for complexes formed by phosphoric acid and its dimer with DMF obtained
before [1].
All ab initio calculations have been based on density functional theory at level of the
B3LYP/6-31++G(d,p) using the software GAUSSIAN 03. An effect of solvent is taken into account
in terms of the CPCM approach. The energy barrier for proton transfer in these complexes was
determined using the potential energy surface scan method. We have examined two cases, where, in
the first case, the O…O distance (R) for the hydrogen bond considered is fixed, and no constraints
are imposed in the second case.
As a result, in the solvent model the H-bonds in all investigated complexes are sizably
stronger than the ones in the gas phase. The H-bonds in complexes may be classified as the strong
H-bonds in (H3PO4)n–base for n=1÷2 and moderately strong H-bonds in H3PO4–(base)m for m=2÷3.
The H-bonding interaction in H3PO4–(base)m becomes slightly weaker with increasing number base
molecules. The H-bond between H3PO4 and DMSO for all cases are significantly stronger than that
found for complexes of this acid with DMF.
Our calculations have shown that spontaneous proton transfer is not observed either. The
calculated energy profiles for the proton transfer represent single well potentials for relaxed
geometry of all investigated complexes both in the gas phase and in the solvent environment.
We have found that the O…O distances is playing an important role in the proton transfer
process. At the corresponding values of this distance the potential energy curves of the proton
transfer have two nonsymmetric minima with respect to the energy barrier for each complex. For all
cases the energy barrier height for the transfer is increased with R. The energies for the proton
transfer in H3PO4–(base)m for m=1÷3 become higher with increasing number base molecules. The
probabilities of proton transfer in (H3PO4)n–base for n=1, 2 is virtually identical. For complexes of
phosphoric acid with DMSO proton transfer is more favored in comparison with the similar
complexes with DMF. The B3LYP–CPCM computations show smaller energy barrier and shorter
O…O distance at which a barrier starts to rise for all complexes.
1. Fedorova I.V. et al. Russ. J. Phys. Chem. A., 2016, 90: 293–299.
This work was financially supported by the Russian Foundation for Basic Research (Project No. 15-
43-03088).
41
M. Ilyina1,2
E. Khamitov1
THE INFLUENCE OF SOLVATION UPON THE
REPRODUCTION OF рК OF URACIL AND ITS
DERIVATIVES 1
Department of physical chemistry, Chemical Faculty, Bashkir State
University, Z. Validi Str., 32, Ufa, Russia 2
Quantum chemistry and molecular dynamics Laboratory, The
department of chemistry and underton technology production, GUP
IPRP RB, Iniciativnaya, 12, Ufa, Russia;
[email protected] Uracils belong to the most important pyrimidines that play a key role in the structure and
functionality of nucleic acids, enzymes and some pharmaceuticals [1]. Quantum-chemical
calculations were carried out using the Gaussian09 Rev. D1 software package. All the structures of
interest were optimized using the density functional theory in approximation of τ-dependent gradient-
corrected functional DFT(TPSS)/6-311+G(d, p). Specific hydration is due to formation of hydrogen
bonds between the solvent and the uracil molecule. Non-specific solvation was taken into account
using the PCM model, both, with and without the SMD option.
Table 1. Experimental and theoretical values of pK for uracil and its derivatives.
Compound pKexp pK*theor pK
**theor The correlation of рКexp/рКtheor
5,6-diOHU 2,83 4,96 5,41
5BrU 8,05 11,28 11,77
5ClU 7,95 10,12 11,59
5COOHU 4,16 8,08 9,75
5FU 7,98 11,68 12,18
5СН3U 9,87 14,10 14,03
5NO2U 5,66 7,30 7,77
5OH6COOHU 2,33 6,76 5,39
5OH6СН3U 8,54 13,95 13,53
5OHU 8,11 12,97 13,83
6NH2U 8,39 12,78 12,41
6ClU 5,67 7,27 8,64
6COOHU 2,07 4,39 4,69
6FU 4,03 7,36 7,31 pKa = ∆G0
deprot/2.303RT, where
6СН3U 9,56 13,77 14,71 ∆G0
deprot= 𝐺0(𝐴−) + 𝐺0(𝐻+) − 𝐺0(𝐻𝐴)
6OHU 3,90 3,97 5,88 G0(H
+) = -265.9 ккал/моль[2]
U 9,43 13,03 13,97 R2(PCM) = 0.87; R
2(PCM(SMD)) = 0.94
*Calculations were performed without the SMD option (with 5 water molecules)
** Calculations were performed with the SMD option (with 5 water molecules)
Thus, it was derived that the use of the SMD option in quantum chemical calculations
drusticly improves the quality of data received (as shown in tabla 1), according to this we can
improve the solvation model and get more precise pK calculation results.
1. Gimadieva A.R. et al. Pharmaceutical Chemistry Journal, 2014, 48: 93-96.
2. Camaioni D.M. et al. The Journal of Physical Chemistry A, 2005, 109: 10795-10797.
This work was supported by the Russian Foundation for Basic Research (project no. 4.299.2014/K)
as a part of the governmental task of Ministry of Education of Russian Federation.
1Calculations were performed on the cluster supercomputer “Enterprise” of Institute of Petroleum
Refining and Petrochemistry
42
V.R. Khairullina
A.Y Gerchikov
VIRTUAL SCREENING OF SOME 4-
((PHENYLTHIO)METHYL-1H-PYRAZOLE AND 3-
((PHENYLTHIO)METHYL)PENTAN-2,4-DIONE
DERIVATIVES WITH A PRONOUNCED ANTI-
INFLAMMATORY ACTIVITY Bashkir State University (Ufa, Russia)
The aim of this work was virtual screening of some 3-((phenylthio)methyl)pentan-2,4-dione
and 3,5-disubstituted 4-((phenylthio)methyl)-1H-pyrazole derivatives (fig.1), and study of their
steric complementarity with rat cyclloxygenase (COX) isoforms site. The structures of the
compounds were represented by professor Akhmetova V.R. (Federal State Institution of Science
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences). It is known that these
compounds have a pronounced fungicidal action under in vivo conditions [1]. Anti-inflammatory
activity may be they additional important effects.
I
II
R1=R2=Et (1), i-Pr (2), t-Bu (3), Ph (4), OEt
(7); R1=Me, R2=Ph (5); R1=OEt, R2=Me (6),
R1=3-subst.-thiophene, R2=CF3 (8)
R1=R2=Me (9), Et (10), Ph (12), i-Pr (13);
R1=Me, R2=Ph (11), R1=3-subst.-thiophene,
R2=CF3 (14)
Fig. 1 – Structures of compounds 1-14.
The research was conducted using molecular docking [1]. Macromolecules with codes 3n8x
and 1pxx [2] were selected as a model of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-
2) respectivelly. There are circuits B and A for COX-1 and COX-2 respectivelly were used in the
simulation. Molecular docking of the ligands structures in the cyclooxygenase isoforms was
performed using program Autodock 4.2 [3]. On the basis of data obtained by molecular docking we
can conclude that structures 3, 4, 5, 11, 12 can be potential inhibitors of both cyclooxygenase
isoforms, and they are promising for further studies as lead compounds with a pronounced anti-
inflammory activity. Becouse this compounds can inhibit cyclooxygenase-1 effectivelly they may
have ulcerogenic effect under in vivo conditions. We have established factors that can stabilize
compounds in the active centers of the isoforms of COX. The aim of our further research is
experimental study of anti-inflammatory activity of these compounds.
The authors thank professor Akhmetova V.R. and researchers Ahmadiev N.S. (Federal State
Institution of Science Institute of Petrochemistry and Catalysis, Russian Academy of Sciences) for
providing the structure of sulfur-containing compounds.
1. Akhmetova V.R. et al. Chemistry of heterocyclic compounds, № 5. С. 806 – 815 (2014).
2. http://www.rcsb.org.
3. http://autodock.scripps.edu/.
The work was executed at financial support of project No. 4.299.2014/K performed in the framework
of the project part of state task of Ministry of education and science of the Russian Federation in the
sphere of scientific activities (project 299, 2014) and RFBR (grant 14-04-97035).
43
V.R. Khayrullina1,
A.R. Gimadieva2,
R.F. Nasjirova1,
A.G. Mustafin1,
F.S. Zarudii3
VIRTUAL SCREENING OF SOME URACIL AS
POTENTIAL DIHYDROPYRIMIDINE
DEHYDROGENASE INHIBITORS 1 Department of Chemistry, Bashkir State University, Zaki Validi
Street, 32, Ufa, Russia; 2 Laboratory of pharmacophore cyclic systems, Ufa Institute of
Chemistry of the Russian Academy of Sciences, prospekt Oktyabrya,
71, Ufa, Russia; 3 Chair of Pharmacology №1, Bashkir State Medical University, Ufa,
Lenin Street, 3, Ufa, Russia;
The steric complementarity of 38 uracil derivatives (Fig. 1) with the dihydropyrimidine
dehydrogenase (DPD) active site was studied by the method of molecular docking with AutoDock
4.2 and AutoDock Vina [1-2]. It is known that these compounds are of low toxicity and are
promising as biologically active substances with a wide spectrum of action [3].
Fig 1. Structural formula of uracil derivative.
The obtained data allow us to conclude that among investigated compounds only three
derivatives of uracil (5-bromouracil, 5-bromo-6-methyluracil and 5-methylamino-6-methyluracil)
binding site of the enzyme sterically are correspond and on the numerical values of the free energies
of binding inhibitors with DPD they to referential uracil and 5-fluorouracil are comparable (Fig. 2).
Therefore, it can be expected that co-administration of 5-fluorouracil in the antitumor drugs will
reduce the speed of biotransformation of the substance and reduce its therapeutic dose. All tested
compounds are promising learning conditions in vitro and in vivo a biologically active substance
with a wide spectrum of pharmacological action.
Fig 2. Potential effective as DPD inhibitors uracil derivative.
1. van Kuilenburg A.B.P. et al. Clinical Cancer Research, 2000, 12, 4705-4712.
2. http://autodock.scripps.edu/.
3. Gimadieva A.R. et al. (2013) Synthesis, biological activity and modification of uracils, Ufa:
Gilem, 176 P.
This work was supported by the RFBR grant 14-04-97035 and project №4.299.2014 / K, running
within the design of the public tasks in the field of Education and Science of the Russian Federation
scientific activity
44
A. Kotomkin1
N. Rusakova 1
V. Turovtsev 1,2
Yu. Orlov 1
INTERNAL ROTATION IN THE 1,6 -
DIFLUORINEHEXANE 1 Department of general physics, Physics Faculty, Tver State University,
Sadovy Per., 35, Tver, Russia 2 Department Of Physics, Mathematics And Information Science, Tver
State Medical Academy, Sovetskaya Str. 4, Tver, Russia;
[email protected] Amendment of many thermodynamic quantities requires accounting for the internal rotation
contributions. In this paper an internal rotation around all C-C bounds in 1,6-difluorinehexane
molecule FСH2-(CH2)4-CFH2 has been studied, and 5 potential functions have been obtained. All
minimums and transition states (TS) were determined. All computations have been done by
GAUSSIAN 03 program with B3LYP/6-311++G(3df,3pd) method.
Cis-structure, finded in the paper [2], with the arrangement of atoms in the plane of carbon
chain, was taken as starting point of rotation. Rotations around equidistant from fluorines C-C
bounds have given equal V(φ).
A rotation FCH2—C5H10F (Illustration 1(a)) shown an existence of gauche+ (g
+) and gauche
-
(g-) conformers. Energy of cis-conformer is higher than energy of gauche-conformers by 1,1
kJ/mole. Consequently structure with g+, g
- arrangement of fluorine is most equilibrium. Below this
rotamer has been used as as starting point of rotation.
A rotation of the FC2H4 tops gives the asymmetric potential functions V(φ) (Illustration 1(b)).
Cis- rotamer corresponds to global minimum on V(φ), whereas energies of g+
and g- are higher than
cis- energy by 5,1 kJ/mole и 4,0 kJ/mole respectively.
As a result of FC3H6-C3H6F rotation asymmetric potential functions V(φ) has been obtained
(Illustration 1(c)). It has two mirror-like g± - conformers, which energies are higher than cis- energy
by 4,3 kJ/mole.
The heights of rotation barriers reach the value 25,1 kJ/mole and exhibit that free rotations
are impossible at normal temperature.
1. Frisch M.J., Trucks G.W., Schlegel H.B. at all. Gaussian 03 (Revision E 0.1 SMP). Gaussian Inc.,
Pittsburgh PA, 2007.
2. Kotomkin A.V., Rusakova N.P., Turovtsev V.V., Orlov. Yu.D. Bulletin of the Tver State
University. Series: Chemistry ,2015, 2, 5-11.
Article was made within the realization of research work «Development of the program complex for
computation of thermodynamic properties of organic compounds» under the treaty with Foundation
for Assistance to Small Innovative Enterprises №9498ГУ/2015 dated 28.15.2015
Illustration 1: 1 Potential functions of internal rotation of the tops FCH2 (a), FC2H4 (b), FC3H6
(c)
45
N. S. Kozina1
M. R. Gainullin1,2
UBIQUITIN SYSTEM IN VIEW OF
COMPUTATIONAL SYSTEMS BIOLOGY 1 Central Research Laboratory, Nizhniy Novgorod State Medical Academy,
Nizhniy Novgorod, Minin Sq. 10/1, 603005, Russia; 2 Institute of Information Technology, Mathematics and Mechanics,
Nizhniy Novgorod State University, Nizhniy Novgorod, Gagarin Av. 23,
603950, Russia.
Post-translational modifications of proteins (PTM) regulate a multitude of critical cellular
processes. Currently, mass spectrometry-based proteomics begun to reveal thousands of sites
targeted for modifications. In spite of these remarkable achievements, the complexity of PTM-driven
regulation requires additional extensive analytics. The computational systems biology offers an array
of powerful resources to connect dynamic landscape of PTMs with up- and downstream cellular
events. The present talk will be focused mainly on the ubiquitylation, a widespread and vital PTM.
The first part provides an overview of recent progress in experimental identification and
quantification of ubiquitylated proteins as well as development of computational resources that
collect and systematize respective data. Next, we will outline some intrinsic features of the ubiquitin
system, which are difficult to discover using experimental methods only. Finally, a possible
application of network biology paradigm aimed to infer causal relationships between ubiquitylation
events and molecular phenotype will be discussed.
46
E.I. Latypov 1
S.A. Neklyudov 2
O. Klimchuk 3
I.S. Antipin 1,2
A. Varnek 2,3
DATABASE ON BENZYL PROTECTION CLEAVAGE
BY HETEROGENEOUS HYDROGENATION IN
CONTINUOUS-FLOW CONDITIONS 1 A.E. Arbuzov Institute of Organic and Physical Chemistry KazSC
RAS, Academician Arbuzov street 10, Kazan, Russia; 2 A.M. Butlerov Institute of Chemistry, Kazan Federal University,
Kremliovskaya street 29, Kazan, Russia; 3 University of Strasbourg, Strasbourg, France;
The one of the actual problem nowadays is prediction of organic reactions conditions.
Hydrogenation is one of the most common and important reactions in the organic chemistry,
significant in the science as well in the industry. In these latter days technologies of the
hydrogenation in continuous-flow conditions develop especially active, due to variety advantages:
an experiment needs minimum quantity of reagents, required time is 15-30 minutes, experiment’s
conditions can be changed easily and experiment is fully automated (from the input of reagents to
products collection stage).
In this work reactions of heterogeneous hydrogenation of aromatic compounds, that containing
benzyl and nitro-group, are researched by using ThalesNano H-Cube reactor. This continuous-flow
reactor allows hydrogenating in automated mode in various conditions (pressure, temperature, flow
rate) with catalysts exchange. The palladium based catalysts (5% Pd/Al2O3, 5% Pd/BaSO4, 5%
Pd/CaCO3(Pb), 10% Pd/C, 20% Pd(OH)2/C) are used. Obtained reaction mixtures are analyzed by
gas chromatography–mass spectrometry (GC-MS).
On the basis of the received data determination of conditions’ influence is planned that allows
predicting optimal conditions for hydrogenation reactions in continuous-flow reactors. That will give
an opportunity for synthetic chemists to choose optimal conditions for hydrogenation reactions
without searching many various experimental conditions.
The work was supported by the Russian Research Foundation, project no. 14-43-00024.
47
V.S. Naumov1
A.A. Avdoshin1
S.K. Ignatov1
DISSOLUTION AND ASSOCIATION OF CHITOSAN
AND ITS COMPLEXATION WITH PROTEIN
SUBSTRATE. MOLECULAR DYNAMICS STUDY 1 Department of Chemistry, Lobachevsky State University of Nizhny
Novgorod, Gagarina Ave 23/5, Nizhny Novgorod, Russia
[email protected] Chitosan (partially N-acetylated poly-1,4-β-D-glucopyranoseamine-2) and its derivatives are
promising molecular encapsulation agents for drug delivery, in particular for protein drugs.
Encapsulation allows implementing oral intake of such drugs. Chitosan shell should protect drug-
molecule from digestive enzymes. Now, the development of this technology is complicated by the lack
of reliable thermodynamic and kinetic data on dissolution of chitosan, its self-association in solution
and complexation with protein substrates. Information about instability constants of chitosan-protein
complexes with various protein substrats are almost absent and the dissolution process and its kinetics
studied mainly by formal-kinetic approach. Experimental study of chitosan are comlpicated by several
factors: chitosan preparations includes water which can influence to value of physicochemical
constants; chitosan is a mixture of polymers with different degree of acetylation of amino-groups and
different molecular weight; for chitosan aqueous solutions arises factor of protonation of unsubstituted
amino-groups [1]. In this context, the molecular dynamic (MD) simulation are one of useful
approaches for determination of reliable thermodinamic and kinetic constants. MD simulation allows
studying the interaction between chitosan chains and other molecules, surfaces or particles on atomistic
level. In addition, the MD approach provide simple ways for establishing of chitosan charactheristics
dependence on the number, type and charge of amino-substituents, the length of polymer chains and
other molecular and atomistic parametrs. In the present MD study, we have studied three processes: (a)
dissolution of chitosan crystal [2] in aqueous medium with different acidity, (b) association of the
dissolved chitosan chains in the alkaline medium, (c) formation of the insulin-chitosan complexes in a
weakly acidic (pH ~ 6,5) medium. Simulated chitosan had molecular weight of 9.6 kDa, the simulation
time was up to 50 ns (1 fs step), NVT-ensemble, T = 300K, Berendsen thermostat. The calculations
were performed with GROMACS 4.6 (CUDA-version) using the force field GROMOS 56ACARBO [3],
specially modified for calculations of polyaminoglucans (56ACHT). The modification was based on
quantum-chemical calculations (HF/STO-3G // B3PW91/6-31++G(d,p)) of group charges and addition
of the structural elements of chitosan and its derivatives to the force field. It is found that dissolution
process begins when the amino groups protonation degree becomes higher than 30% (pH~6,8), in a
good agreement with experimental data. The dissolution rate increases linearly with increasing degree
of protonation. The dependence between the polymer chain length and kinetic parametrs of dissolution
was established. The approximation of the kinetic parameters of dissolution to the infinite polymer
chain length was found. The characteristic time of the association of chitosan from homogeneous
solution was determed. Energy of chitosan chain coordination with the insulin dimer evaluated by the
PMF method was of 11 kcal/mol at pH=6.5.
1. Wang, Q.Z., et al. Carbohydrate Polymers, 2006. 65(2): p. 194-201
2. Yui T., et al. Macromolecules, 1994. 27, 7601.
3. Hansen H.S., Hünenberger P.H. J Comput Chem, 2011, 32, 998
This work was supported by the RFBR (Project No. 14-03-00585)
48
K.A. Romanova
Yu.G.Galyametdinov
QUANTUM CHEMISTRY APPROACHES FOR LN-
CONTAINING FUNCTIONAL MATERIALS DESIGN Physical and colloid chemistry department, Institute of polymers, Kazan
National Research Technological University, Karl Marx Str. 68, Kazan,
Russia
[email protected] Composite materials based on lanthanide(III) complexes and conjugated polymers can be
used as effective emitting layers in organic light-emitting diodes. The luminescence efficiency of
such composite materials depends on the relative positions of the excited states of the polymer host,
the ligands and the emitting Ln(III) ion. The use of liquid-crystalline Ln(III) complexes with high
luminescence efficiency can add unique properties due to their possibility to orient under the
influence of external electric and magnetic fields [1]. In this work the luminescence efficiency of
some composite materials based on liquid-crystalline Ln(III) complexes with different ligand
environment and conjugated polymers was revealed.
Geometry optimization of liquid-crystalline Ln(III) complexes and monomers of the
polymers that are widely used in optoelectronic devices was made by the DFT method and PBE
functional. Simulation of optical properties of Ln(III) complexes included the calculations of UV
spectra using Sparkle method. The energies of the excited states were obtained by TDDFT and CIS
methods. The calculated IR, NMR spectra and excited states were confirmed experimentally. On the
basis of the calculated excited states, the energy level diagrams were constructed and the main
channels of intramolecular energy transfer were revealed. The effectiveness of energy transfer from
the polymer excited levels to the ligand levels in Ln(III) complexes was evaluated. Polymers that
provide the most efficient energy transfer and, consequently, the best emitting properties of Ln(III)
functional materials were selected (Figure 1).
Figure 1. Energy-transfer pathways in Eu(III) composite material
The calculations were performed using the facilities of the Joint Supercomputer Center of
Russian Academy of Sciences and the Supercomputing Center of Lomonosov, Moscow State
University [2].
1. Romanova K.A. et al. Journal of Physical Chemistry A, 2014, 118: 11244-11252.
2. Voevodin V.V. et al. Open Systems J., 2012, 7: 36-39.
This work was supported by the grant of the President of the Russian Federation for the state
support of the young Russian scientists - candidates of sciences (No МК-7320.2016.3).
49
R. Shayakhmetova
E. Khamitov
ADSORPTION ACTIVITY OF Π-Π COMPLEXES OF
GRAPHENE WITH PHENOL DERIVATIVES AND
ANILINE. DFT STUDY WITH EMPERICAL
DISPERSION CORRECTION
Chair of Physical Chemistry and Chemical Ecology, Bashkir State
University, Validy Str., 32, Ufa, Russia
In present paper the energy and geometric characteristics of graphene complexes with aniline
and benzene derivatives was estimated. Calculations were performed using a Gaussian09
approximation PBE0/6-31G(d,p)1 with emperical dispersion correction GD3BJ
2. .
As the substrate for the study of the adsorption was taken 14.055x13.597Å size fragment
graphene. A test molecule in the original structures are located parallel to the plane of graphene at a
distance of 3Å (Fig. 1).
Fig. 1. The equilibrium geometric structure of π-π complex of graphene with phenol
Based on the rows of stability found that the most stable complex graphene forms with o-
nitroaniline (Table. 1).
Table 1. Energy of graphene complexes formation with aniline and phenol derivatives, kJ/mol.
test molecule Eform test molecule Eform
phenol -52.1 3,5-dimethylphenol -79.4
o-chlorophenol -57.7 m-nittroaniline -83.0
2,4-dichlorophenol -72.0 m-chloraniline -67.4
p-nitrophenol -76.5 p-nitroaniline -83.2
o-nitrophenol -76.2 o-chloroaniline -72.5
2,6-dimethylphenol -68.1 p-chloroaniline -73.8
2,4-dinitrophenol -95.4 2,4-dinitroaniline -95.5
o-ethylphenol -61.4 p-chlorophenol -100.0
o-methylphenol -66.8 o-nitroaniline -121.5
1. Adamo, C. et al. The Journal of Chemical Physics. 1999, 110: 6158-6170.
2. Grimme, S. et al. J Comput Chem. 2011, 32: 1456-65.
The work was financially supported by the project 16-13-10257 of Russian Science Foundation. ). The
authors are grateful to the Center of Collective Use “Chemistry” (Ufa Institute of Chemistry of
Russian Academy of Sciences) and Institute of Petroleum Refining and Petrochemistry of RB for the
access to the cluster supercomputer.
50
K.E. Shpilevaya1,
N.I.Giricheva1,
M.S.Fedorov1,
S.A.Syrbu1
THE SEARCH FOR POTENTIAL MESOGENS. Н-
BONDED COMPLEXES. 1 Ivanovo State University, Faculty of Biology and Chemistry
The rapid advancement of technology has imposed new requirements on liquid crystal
materials. The molecular design of mesogens has been gradually losing its potential. The reason for
this is that the range of potential synthons for designing calamitic mesogens has been restrained and
well-known. The mesogens of different chemical nature (e.g., discotic mesogens,
metallomesogens, etc.) do not always enable the development of liquid crystal materials with
targeted properties. Among the specific interactions in liquid crystal complexes, hydrogen bonding
excites special interest. This is due to a particular combination of its properties i.e. its high strength
and stereospecificity on the one side and dynamics on the other side.
This paper presents the results of our study of the structure of a H-bonded complex of p-n-
propyloxycinnamic acid (А) and pyridine ether of p-n-propyloxybenzoic acid (В), as well as the
determination of characteristics of intermolecular hydrogen bonds in a H-bonded complex.
When modeling a H-bonded complex, we used the most energetically favourable conformers
of the А and В molecules. The geometric parameter optimization was performed for all conformers
of separate molecules and for the H-bonded complex, and molecular vibrational frequencies were
calculated using the DFT/B97D method (taking into account the dispersive interaction) with 6-
311++G** basis set.
Fig.1. H-bonded complex formed from p-n-propyloxycinnamic acid (А) and pyridine ether
of p-n-propyloxybenzoic acid (В)
The main body of the А molecule is structurally rigid, hindered internal rotation of the
pyridine fragment is possible in the B molecule (V0=0.4 kcal/mol), which occurs with saving the
director course and dipole moment of the molecule B. The elements of polarizability tensor for the
complex: αxx=716.6; αyy=323.7; αzz=224.8 have been determined.
The energy of interaction between the molecules А and В, which amounted to -14.5
kcal/mol (-13.8 kcal/mol, BSSE corrected for basis set superposition), was calculated using the
formula (where SP –Single Point energy calculations):
∆Eint=E complex(Opt)-(EА(SP) + EВ(SP))
The obtained characteristics of the complex are indicative of the formation of strong
intermolecular hydrogen bonding and high anisotropy of the electron density.
This scientific work was financially supported by the Ministry of Education and Science of the
Russian Federation (Basic part, Project №3474).
A B
51
I. Yu. Zhukov1,2
N. D.Prakhov1
E. L. Guryev1,2
A. L. Chernorudskiy1
M. R. Gainullin1,3
TARGETING UBE2N HETERO-DIMERIZATION: IN
SEARCH OF COMPOUNDS TO MANIPULATE CELL
SURVIVAL PATHWAYS 1
Central Research Laboratory, Nizhniy Novgorod State Medical
Academy, Minin Sq. 10/1, Nizhniy Novgorod, Russia; 2 Institute of Biology and Biomedicine, Nizhniy Novgorod State
University, Gagarin Av. 23, Nizhniy Novgorod, Russia; 3 Institute of Information Technology, Mathematics and Mechanics,
Nizhniy Novgorod State University, Gagarin Av. 23, Nizhniy
Novgorod, Russia;
[email protected] UBE2N (known also as ubiquitin-conjugating enzyme Ubc13) is the active E2-subunit of an
ubiquitin-protein ligase that catalyzes the synthesis of K63-linked multi-ubiquitin chains (multi-K63-
Ub). This type of multi-ubiquitylation does not lead to protein degradation by the 26Sproteasome, but
critically regulates processes that generally enhance the survival of cells and organisms in response to
certain forms of stress, such as DNA damage or exposure to infectious agents. UBE2N functions
together with one of its 2 cofactors – UEV-1 (UBE2V1) and Mms2 (UEV2, UBE2V2). Hetero-
dimeric UBE2N/UEV1A complex, in conjunction with the E3 enzyme TRAF6, induces multi-K63-
Ub-dependent TAK1 activation. Subsequently, TAK1 phosphorylates and activates the IKK complex,
which phosphorylates I--B protein, leading to I--B degradation, followed by NF--B activation. In
complex with the Mms2, UBE2N promotes the multi-K63-ubiquitylation at sites of DNA double-
strand breaks, leading to the recruitment of repair proteins to the DNA lesions and thereby contributes
to the survival of cells after DNA damage. In the absence of any cofactor, ubiquitin moieties are
transferred to UBE2N´s own lysine residue (auto-ubiquitylation). The mechanism and physiological
role of UBE2N autoubiquitylation is not well studied. In present survey we looked for small ligands
capable to disturb specific interactions between UBE2N and its adaptor protein Mms2 using a high-
throughput virtual screening approach. Additionally, we designed a simple enzymatic system for
experimental testing of identified drug-like substances.
This work was supported by RFBR grant 14-04-01199.
52
CONTENT
pages
General Information 1
Program
Abstracts
3
A. Tropsha 6
J. Gasteiger 7
A. Varnek 8
O. Klimchuk, A. I. Lin, T.I.Madzhidov, R. I. Nugmanov, I. Antipin, A. Varnek 9
S.V. Lushchekina, P. Masson, A.V. Nemukhin, E.E. Nikolsky,
S.D.Varfolomeev 10
Y. Gilad,K. Nadassy,H. Senderowitz
11
P. Polishchuk 12
T. Makarova 13
M. Glavatskikh, T. Madzhidov, V. Solov’ev, D. Horvath, G. Marcou, A. Varnek
14
O. Titov, D. Shulga, V. Palyulin, N. Zefirov 15
G. Marcou, B. Viira, P. Sidorov, D. Horvath, U. Maran, E. Davioud-Charvet, A.
Varnek 16
V. Solov’ev, M. Glavatskikh, D. Horvath, G. Marcou, A. Varnek 17
Y. D. Loginova, S. Z. Vatsadze, D. A. Shulga 18
T.R. Gimadiev ,T.I. Madzhidov, R.I. Nougmanov, A. Varnek 19
S. A. Dzhabieva, S.V. Kurbatova 20
N. I. Akberova, A. A. Zhmurov, T. A. Nevzorova, R. I. Litvinov 21
R. Ayupov, N. Akberova, M. Yusupov 22
V. G. Tsirelson 23
Yu.A.Ustynyuk 24
R. R. Nazmutdinov, M. D. Bronshtein, T. T. Zinkicheva, D. V. Glukhov 25
I. I. Baskin 26
M.Yu. Balakina, O.D. Fominykh
27
K. Klimenko, G. Marcou, D. Horvath, A.Varnek 28
V. Torbeev 29
T.I. Madzhidov, T.R. Gimadiev, R.I. Nugmanov, I.I. Baskin, I.S. Antipin, A.
Varnek 30
T. Salah, S. Belaidi, N. Melkemi, I. Daoud
31
S.Shermukhamedov, V. Glukhov, R. Nazmutdinov 32
A. S. Loginova, S. K. Ignatov, L. V. Moskaleva, M. Bäumer 33
N.A. Burmistrova,I. Vakulin 34
N.A. Nekrasova, S.V. Kurbatova 35
M. K. Glagolev, A. A. Lazutin, V. V. Vasilevskaya 36
R.I. Nugmanov,T.I. Madzhidov, A. Varnek
37
Adilova F.T., Ikramov A.A. 38
F.T Adilova, R.R. Davronov, U.U.Jamilov, Sh.N. Murodov 39
I. Fedorova 40
M. Ilyina, E. Khamitov
41
V.R. Khairullina, A.Y Gerchikov 42
V.R. Khayrullina, A.R. Gimadieva, R.F. Nasjirova, A.G. Mustafin, F.S. Zarudii 43
53
A. Kotomkin, N. Rusakova, V. Turovtsev , Yu. Orlov 44
N. S. Kozina, M. R. Gainullin 45
Latypov E.I., Neklyudov S.A., Klimchuk O., Antipin I.S., Varnek A. 46
V.S. Naumov, A.A. Avdoshin, S.K. Ignatov 47
K.A. Romanova, Yu.G.Galyametdinov 48
R. Shayakhmetova, E. Khamitov 49
K.E. Shpilevaya, N.I.Giricheva, M.S.Fedorov, S.A.Syrbu 50
I. Yu. Zhukov, N. D.Prakhov, E. L. Guryev, A. L. Chernorudskiy, M. R.
Gainullin
51
1