Download - modeling melting points
![Page 1: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/1.jpg)
COLLECTING, CURATING, AND MODELING MELTING POINTS
Andrew Lang
Professor of Mathematics
Oral Roberts University
![Page 2: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/2.jpg)
![Page 3: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/3.jpg)
Open Drug Discovery for Neglected Diseases
MalariaSchistosomiasis Gram positive bacteriaBreast Cancer
![Page 4: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/4.jpg)
Drugs for neglected diseases
need to be…
![Page 5: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/5.jpg)
cheap and…
![Page 6: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/6.jpg)
easy to make.
![Page 7: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/7.jpg)
docking
combinatorial library
synthesis
solvent selection
recrystallization
biologicalassay
solubility models
solubility data
melting point models
melting point data
The big picture
![Page 8: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/8.jpg)
docking
combinatorial library
synthesis
solvent selection
recrystallization
biologicalassay
solubility models
solubility data
melting point models
melting point data
Oral Roberts University undergraduate research
![Page 9: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/9.jpg)
Cameron NeylonBiophysicist RAL
David BulgerMD/PhD Student
Tennessee
Solubility Measurements and Ugi Product Synthesis at ORU,
Drexel, and RAL
Submeta ONS Award Winner, BOE Award Winner
Supervisors: Robert Stewart, Lois Ablin, Bill Collier, Joel
Gaikwad, Jean-Claude Bradley, and Cameron Neylon
![Page 10: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/10.jpg)
Lizzie ClarkNursing Major
Lacey CondronChemistry Major
Samantha Gaines, Lizzie Clark, and Lacey Condron
Solubility Measurements and Solubility Modeling at ORU
Supervisors: Ken Weed, Lois Ablin
![Page 11: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/11.jpg)
Daryl Charron, Alejandro Hernandez, Maria Hernandez, Jesse Patsolic, Matthew Wilson
Cluster Computer Construction and In-Silico
Docking at ORU
Supervisors: Ken Preston
![Page 12: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/12.jpg)
docking
combinatorial library
synthesis
solvent selection
recrystallization
biologicalassay
solubility models
solubility data
melting point models
melting point data
Let’s focus
![Page 13: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/13.jpg)
Early models, before 2005 were…
![Page 14: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/14.jpg)
…specialized1979 Martin – disubstituted benzenes1987 Hanson – normal alkanes1988 Needham – normal and branched alkanes1990 Abramowitz – non-hydrogen bonded benzenes1991 Dearden – anilines1993 Katritzky – aldehydes, amines, and ketones1994 Simamora – rigid aromatic1996 Charlton – alkanes1996 Katritzky – pyridines1999 Zhao – aliphatic2001 Chickos – homologous series2003 Bergstrom – druglike (N = 277, r2 = 0.54)
![Page 15: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/15.jpg)
In 2005…
…everything changed
![Page 16: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/16.jpg)
MDPI - cheminformatics.org
Karthikeyan 2005 N = 4173, r2 = 0.65
![Page 17: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/17.jpg)
PHYSPROP
Clark 2005 N = 6257, r2 = 0.61
![Page 18: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/18.jpg)
Recent melting point models use these datasets…
…never reproducing r2 = 0.65 (0.47 – 0.56)
![Page 19: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/19.jpg)
Even though [a] melting point can be measured accurately, its prediction has been a notoriously difficult problem.
![Page 20: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/20.jpg)
We began measuring, collecting, and curating melting points in the Fall of 2010
![Page 21: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/21.jpg)
Jean-Claude Bradley’sChemical Information Retrieval
Course at Drexel
567 curated and referenced measurements from Fall 2010 Chemical Information Retrieval course
![Page 22: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/22.jpg)
Most popular data sources…
…chemical vendors
![Page 23: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/23.jpg)
Alfa Aesar donates ~13,000melting points to the public domain
![Page 24: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/24.jpg)
collection
curation
modelingvalidation
measurement
ONS melting point
workflow
![Page 25: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/25.jpg)
Collection: Open Datasource data points curated values source year data type
Bell 2483 1631 1995 donated-CC0
Bergstrom 277 277 2003 open
MDPI-Karthikeyan 4450 4084 2005 open
Hughes 287 262 2008 open
Oxford-MSDS 3217 1481 2010 open
Drugbank 875 875 2011 open
Griffiths 3757 278 2011 donated-CC0
Alfa Aesar 12986 8739 2011 donated-CC0
PHYSPROP 11645 9694 2011 donated-CC0
ONS 471 471 2012 open
27792 curated measurements for 19410 compounds
![Page 26: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/26.jpg)
Curation is…
…lots of hard, tedious work(Jean-Claude Bradley and Antony Williams)
Antony Williams – RSC ChemSpider
![Page 27: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/27.jpg)
Inconsistencies and SMILES problems within the “high trust level” MDPI dataset
![Page 28: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/28.jpg)
PHYSPROP Structure Errors (Incorrect Valence)2315 out of 43543 contained pentavalent nitrogens
![Page 29: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/29.jpg)
PHYSPROP Errors: Structure displayed is for the neutral compound dopamine but the associated CAS Number and
chemical name in the file are for the hydrobromide salt.
![Page 30: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/30.jpg)
Common errorsunit errors: Kelvin/Celsius, Fahrenheit/Celsius
bad SMILES (non-rendering, hypervalency)
salts associated with SMILES for free base
using boiling point for melting point
![Page 31: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/31.jpg)
Some melting points can’t be resolved only with literature: 4-benzyltoluene
![Page 32: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/32.jpg)
Open lab notebook page measuring the melting point of 4-benzyltoluene
![Page 33: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/33.jpg)
Modeling – All Data
Melting Point Model
CDKdescriptor calculator
Rstatistical computing
melting point data
![Page 34: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/34.jpg)
MP Model N = 19515, r2 = 0.80
use this model
![Page 35: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/35.jpg)
Modeling – Highly Curated Subset
compoundsdoubleplusgoodsingle
CDKdescriptor calculator
Rstatistical computing
data
Melting Point Model
![Page 36: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/36.jpg)
MP Model N = 2704, r2 = 0.83
![Page 37: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/37.jpg)
Straight chain carboxylic acids from 1 to 10 carbons
Straight chain alcohols from 1 to 10 carbons
Comparison of model with double+ validated measurements
![Page 38: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/38.jpg)
Cyclic primary amines from 3 to 6 carbons cyclobutylamine flagged for measurement
only single source available
![Page 39: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/39.jpg)
Publication of double+ validated melting point dataset
…as a preprint
![Page 40: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/40.jpg)
Publication of double+ validated melting point dataset
…as a book
![Page 41: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/41.jpg)
Data and model deployed…
…on the web
web service
![Page 42: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/42.jpg)
…in Google spreadsheets
![Page 43: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/43.jpg)
…as an app
![Page 44: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/44.jpg)
Use case: recrystallizing dibenzalacetone
Can the solvents used to recrystallize compounds in organic teaching labs be improved?
Trans-dibenzalacetone
Aldol condensation between two molecules of benzaldehyde and one molecule of acetone
[Matthew McBride: Undergraduate Research Assistant - Drexel]
![Page 45: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/45.jpg)
Dibenzalacetone First recrystallized in ethyl acetate in 1906: Straus
and Ecker, Ber. 39, 2988 (1906) Recrystallized in ethyl acetate in Organic Syntheses
![Page 46: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/46.jpg)
Organic Teaching Labs
Recommended recrystallization solvent: ethyl acetate.
(http://classes.kvcc.edu/chm230/mixed%20aldol%20condensation.pdf
(http://www.xula.edu/chemistry/documents/orgleclab/Aldol_notes.pdf)
![Page 47: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/47.jpg)
Recrystallization AppEnter compound identification and desired parameters
![Page 48: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/48.jpg)
How does it work?
1. Look up the solvent boiling point
2. Look up the room temperature solubility or predict it via measured or predicted Abraham descriptors
3. Look up the solute melting point or predict it via a model
4. Use the melting point and the solubility at room temperature to predict the solubility at boiling
5. Calculate the predicted recrystallization yield
![Page 49: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/49.jpg)
ResultsLists solvents and their predicted recrystallization yield.
Prediction is generated by the temperature dependent solubility curves.
![Page 50: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/50.jpg)
Comparison ethyl acetate (predicted yield of 72%) vs ethanol
(predicted yield of 93%) ethyl acetate
ethanol
0.09M
1.1M
0.62M
2.06M
![Page 51: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/51.jpg)
Dibenzalacetone derivatives docking against tubulin (paclitaxel site)
![Page 52: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/52.jpg)
Example Derivatives of dibenzalacetone may be synthesized
by altering the aldehyde used From a library of derivatives, the following
compound was the top hit for the docking site of Taxol
Uses phenanthrene-9-carboxaldehyde
![Page 53: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/53.jpg)
Search Literature Perform a Reaxys search to determine availability
of synthesis procedures
No results
[Matthew McBride: Undergraduate Research Assistant - Drexel]
![Page 54: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/54.jpg)
Synthesis and recrystallization solvents chosen using ONS models
Used methanol and benzene
Melting Point: 264-265°C
(http://usefulchem.wikispaces.com/EXP286)
[Matthew McBride: Undergraduate Research Assistant - Drexel]
![Page 55: modeling melting points](https://reader036.vdocument.in/reader036/viewer/2022062418/554e9aebb4c905fc368b5213/html5/thumbnails/55.jpg)
AcknowledgementsORU Biology and Chemistry FacultyJean-Claude Bradley (Drexel)Cameron Neylon (RAL)Antony Williams (RSC ChemSpider)Evan Curtin (Drexel)Matthew McBride (Drexel)
ORU research assistants: David Bulger, Daryl Charron, Lizzie Clark, Lacey Condron, Samantha Gaines, Alejandro Hernandez, Maria Hernandez, Jesse Patsolic, and Matthew Wilson