Binary mixture of Butanol(1) and Heptane (2)

at 50° C

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0x1 Mole fraction of 1-butanol (1)

ln(

)

1-Butanol (calculated)n-Heptane (calculated)1-Butanol (experiment)n-Heptane (experiment)

Andreas KlamtCOSMOlogic GmbH&Co.KG, Leverkusen, Germanyand Inst. of Physical Chemistry, University of Regensburg, Germany

COSMO-RS: From quantum chemistry

to Cheminformatics

gas phase

latitudes ofsolvation

water

alkanes

horizon ofCOSMO-RS

horizon of gas-phase methods

solid

phase

Thermophys ical data prediction methods

Quantum Chemistrywith dielectric

solvation models like PCM

or COSMO

quantumchemistry

-OH

-OCH3

-C(=O)H

-CarH-CarH -C

arH-Car

-Car -Car

Group contribution methodsUNIFAC, CLOGP, LOGKOW, fingerprints,.. etc.

simple, well explored solvents

fitted parameters: CLOGP:~ 1500UNIFAC: ~5000 +50% gaps

≠

MD / MCforce-fieldsimulations

MD/MC

softbiomatter

Dielectric Continuum Solvation Models (CSM) Dielectric Continuum Solvation Models (CSM)

- Born 1920, Kirkwood 1934, Onsager1936

- Rivail, Rinaldi et al. - Katritzky, Zerner et al.- Cramer, Truhlar et al. (AMSOL)- Tomasi et al. (PCM) - Orozco et al. - Klamt, Schüürmann (COSMO) e.g. DMol3/COSMO and others

- promising results for solvents water, alkanes, and a few other solvents

- empirical finding: cavity radii should be about 1.2 vdW-radii

solute molecule embedded in a dielectric continuum,self-consistent inclusion of solvent polarisation

(screening charges) into MO-calculation (SCRF)

But CSMs are basically wrong and give a poor, macroscopic description of the solvent !

Density Functional Theory (DFT)is appropriate level of QC!COSMO almost as fast as gasphase!programs: DMol3, Turbomole,

Gaussian98_release2001up to 25 atom:< 24 h on LINUX PC

COSMO = COnductor-like Screening Model,just a (clever) variant of dielectric CSMs

Why are Continuum Solvation Models Why are Continuum Solvation Models wrong for polar molecules in polar solvents? wrong for polar molecules in polar solvents?

-only electronic polarizibility-homogeneously distributed-linear response up to very high fieldsdielectric continuum theory should be reasonably applicable

-discrete permanant dipoles -mainly reorientational polarizibility-linear response requires Ereor << kT- typically Ereor ~ 8 kcal/mol !!!no linear response, no homogenityno similarity with dielectric theory

gas phase

latitudes ofsolvation

water

acetone

alkanes

horizon ofCOSMO-RS

horizon of gas-phase methods

solid

statebridge ofsymmetry

How to come to the latitudes of solvation?

QM/MMCar-Parrinello

-OH

-OCH3

-C(=O)H

-CarH-CarH -C

arH-Car

-Car -Car

Group contribution methodsUNIFAC, CLOGP, LOGKOW, etc.

Quantum Chemistrywith dielectric

solvation models like COSMO

or PCM

MD / MCsimulations

native home of computational chemistry

COSMO-RS

state of ideal screening home of COSMOlogic

1) Put molecules into ‚virtual‘ conductor (DFT/COSMO)COSMO-RS:COSMO-RS:

++++++

____ _

σ '

σ

σ >> 0σ ' << 0(1)

(2) hydrogen bond

electrostat. misfit

ideal contact

3) Remove the conductor on molecular contact areas (stepwise) and ask for the energetic costs of each step.

2) Compress the ensemble to approximately right density

(3) specificinteractions

2)'(2

')',( σσασσ += effmisfit aG

}',0min{)()',( 2hbhbeffhb TcaG σσ σσσ +=

In this way the molecular interactions reduce to pair interactions of surfaces!

Water

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020σ [e/A2]

pwat

er(s

) (am

ount

of s

urfa

ce)

Screening charge distribution on molecular surface reduces to "σ-profile"

COSMO-RS COSMO-RS For an efficient statistical thermodynamics reduce the ensemble of

molecules to an ensemble of pair-wise interacting surface segments !

✪

0

5

10

15

20

25

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020

σ [e/A2]

pX ( σ)

Water

Methanol

Acetone

Benzene

Chloroform

Hexane

Screening charge distribution on molecular surface reduces to "σ-profile"

A. Klamt, J. Phys. Chem., 99 (1995) 2224COSMO-RS COSMO-RS For an efficient statistical thermodynamics reduce the ensemble of

molecules to an ensemble of pair-wise interacting surface segments !(same approximation as is UNIFAC)

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Mole fraction of acetone (1)

ln( γ

)

Acetone (calculated)

Chloroform (calculated)

Acetone (experiment, Rabinovichet al.)Chloroform(experiment,Rabinovich et al.)Aceton (experiment, Apelblat etal.)Chloroform (experiment, Apelblatet al.)

0

5

10

15

20

25

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020

σ [e/A2]

pX ()

Acetone

Chloroform

Because their Because their σσ-profiles are -profiles are almost complementary!almost complementary!

Why do acetone and chloroform Why do acetone and chloroform like each other so much?like each other so much?

• Replace ensemble of interacting molecules by an ensemble S of interacting pairs of surface segments• Ensemble S is fully characterized by its σ-profile pS(σ)

( pS(σ) of mixtures is additive! -> no problem with mixtures! )• Chemical potential of a surface segment with charge density σ is exactly(!) described by:

( )µ σ σ σσ σ µ σ

S Sint SkT d p

EkT

( ) ln ' ' exp( , ') ( ')

= − −−

∫

chemical potential of solute X in S:

( ) ( ) SS

XXS AkTpd lnλσµσσµ −= ∫

activity coefficients → arbitrary liquid-liquid equilibria

Statistical ThermodynamicsStatistical Thermodynamics

combinatorial contribution:solvent size effects

σ-potential:affinity of solvent forspecific polarity σ combX

S,γ

σσ-profiles -profiles and and

σσ-potentials of -potentials of representative liquidsrepresentative liquids

-0.50

-0.30

-0.10

0.10

0.30

0.50

0.70

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020σ [e/A2]

µX ( σ) [

kJ/m

ol A

2 ]

Water

Methanol

Acetone

Benzene

Chloroform

Hexane

hydrophobicity

affinity for HB-donors

affinity for HB-acceptors

0

5

10

15

20

25

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020

σ [e/A2]

pX ( σ)

Water

Methanol

Acetone

Benzene

Chloroform

Hexane

a) DGhydr (in kcal/mol)

-11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3

-2

-1

0

1

2

b) log Pvapor (in bar)-4 -3 -2 -1 0 1 2

-2

-1

0

1

2

c) log KOctanol/Water-2 -1 0 1 2 3 4 5 6

-2

-1

0

1

2

d) log KHexane/Water-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7

-2

-1

0

1

2

e) log KBenzene/Water

-4 -3 -2 -1 0 1 2 3 4 5-2

-1

0

1

2

f) log KEther/Water-3 -2 -1 0 1 2 3

-2

-1

0

1

2

alkanes alkenes alkines alcohols ethers carbonyls esters aryls diverse amines amides N-aryls nitriles nitro chloro water

Results of parametrization based on DFT (DMol3: BP91, DNP-basis

650 data17 parametersrms = 0.41 kcal/mol

A. Klamt, V. Jonas, J. Lohrenz, T. Bürger, J. Phys. Chem. A, 102, 5074 (1998)

meanwhile:COSMOtherm5.0 with Turbomole BP91/TZVPrms = 0.36 kcal/mol

Res

idua

ls

Applications to Phase Diagrams and AzeotropesApplications to Phase Diagrams and Azeotropes

Binary mixture of Butanol(1) and Heptane (2)

at 50° C

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0x

y CalculatedExperiment

Binary mixture of Butanol(1) and Heptane (2)

at 50° C

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0x1 Mole fraction of 1-butanol (1)

ln(

)

1-Butanol (calculated)n-Heptane (calculated)1-Butanol (experiment)n-Heptane (experiment)

Binary mixture of ethanol (1) and benzene (2)

at 25° C

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0x

yCalculatedExperiment

Binary Mixture of 1-butanol (1) and water

at 60° C

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0x

y

CalculatedExperiment

miscibility gap

November 2002: COSMOtherm wins the VLE prediction contest of Nat. Inst. of Standards (NIST)

and American Inst. of Chem. Engineers (AICHE)

sigma-profiles

0

2

4

6

8

10

12

14

-0.02 -0.01 0 0.01 0.02screening charge density [e /A²]

vanillin

w ater

acetone

sigma-potential

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

-0.02 -0.01 0 0.01 0.02

Chemical Structure

Quantum ChemicalCalculation with COSMO

(full optimization)

σ-profiles of compounds

other compounds

ideally screened moleculeenergy + screening charge distribution on surface

DFT/COSMO COSMOtherm

σ-profile of mixture

σ-potential of mixture

Fast Statistical Thermodynamics

Equilibrium data:activity coefficientsvapor pressure,solubility,partition coefficients

Phase Diagrams

Database of COSMO-files

(incl. all common solvents)

Flow Chart of COSMO-RS Binary Mixture of

Butanol and Water at 60° C

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0x

y Calculated

Experiment

miscibility gap

gas phase

latitudes ofsolvation

water

acetone

alkanes

horizon ofCOSMO-RS

horizon of gas-phase methods

solid

statebridge ofsymmetry

How to come to the latitudes of solvation?

QM/MMCar-Parrinello

-OH

-OCH3

-C(=O)H

-CarH-CarH -C

arH-Car

-Car -Car

Group contribution methodsUNIFAC, CLOGP, LOGKOW, etc.

Quantum Chemistrywith dielectric

solvation models like COSMO

or PCM

MD / MCsimulations

native home of computational chemistry

COSMO-RS

state of ideal screening home of COSMOlogic

Extension of COSMOtherm to multi-conformations

COSMOtherm can treat a compound as a set of several conformers- each conformer needs a COSMO calculation - conformational population is treated consistently

according to total free energy of conformers (by external self-consistency loop)

Unfortunately, many molecules have more than one relevant conformation

σ -profiles of glycerol conformers

0

2

4

6

8

10

12

14

-0.02 -0.015 -0.01 -0.005 0 0.005 0.01 0.015 0.02σ

h2oglycerol4_cosmoc01glycerol2_cosmoc02glycerol3_cosmoc04glycerol1_cosmoc05glycerol0_cosmoc03glycerol3_cosmoc05glycerol3_cosmoc03

z

Conformational effects for glycerollowest COSMO conformerall 3 donors are bound in one 6-ring and two 5-rings,also least polar conformer39% in octane 9% in acetone

2nd COSMO conformer Ecosmo=+0.37 kcal/mol Ediel =+2 kcal/mol1 free donor, two bound in one 6-ring and one 5-rings 16% in octane 8% in acetone

7th COSMO conformer Ecosmo=+1.3 kcal/mol Ediel =+3.3 kcal/mol2 free donors, one bound in strong 6-ring(represents ~4 similar conformations) 2% in octane41% in acetone

partition coefficient between acetone and octone:

logKAO = -3.3 (lowest conformer)logKAO = -4.0 (conformer ensemble)

difference of 0.7 log-units ≈ 1 kcal/mol

Conclusions:

- Conformational effects can be important for the detailed understanding of phase equilibria

- In most cases one conformation dominates in all phases

- Effects are especially large for molecules with sub-optimal intramolecular HBs in solvents having strong HB acceptors, but a deficit of HB-donors.

-Tautomers can be considered as a kind of conformers.

-Unfortunately the DFT level of QC is not always reliable regarding the energy differences between conformers and even more between tautomers. Energy corrections may be required.

„Conformational analysis of cyclic acidic α-amino acids in aqueous solution - an evaluation of

different continuum hydration models."by Peter Aadal Nielsen, Per-Ola Norrby, Jerzy W. Jaroszewski, and Tommy Liljefors(private comm., Ph.D. thesis)Method Solvent rms rms (4 points) Max Dev Model (kJ/mol) (kJ/mol) (kJ/mol)AM1 SM5.4A 4.6 5.6 9.2PM3 SM5.4P 13.6 16.2 20.5AM1 SM2.1 7.4 9.0 16.7HF/6-31+G* C-PCM 3.1 3.8 5.9HF/6-31+G* PB-SCRF 4.7 5.8 8.8AMBER* GB/SA 13.2 16.2 24.3MMFF GB/SA 18.5 19.9 31.4

BP-DFT/TZVP COSMO-RS 2.2 2.6 4.8COSMO-RS was evaluated as a blind test !!!

Water Solubility log(xH2O)calculated with COSMOtherm

-13

-12

-11

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

-13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1Calculated

Expe

rimen

t

DGfus < 0

DGfus > 0

McFarland Test Set

questionable

R2= 0.90 rms=0.66n = 150

logSXS = (µX

X-µXS+ min(0,∆ Gfus))/1.365

∆ GXfus = 0.54 µX

water - 0.18*NXringatom +0.0029*volume

Dataset taken from Jorgensen and Duffy (BOSS)

Stable model: No changes required for pesticides!A.Klamt, F. Eckert, M. Hornig, M. Beck, and T. Bürger: J. Comp. Chem. 23, 275-281 (2002)

COSMOtherm prediction of drug solubility in diverse solvents(blind test performed with Merck&Co., Inc., Rahway, NJ, USA)

all predictions are relative to ethanol

solvents:

ButanolTriethylamineAcetonitrileEthanolAcetoneChlorobenzeneTolueneHeptaneMethanolEthyl AcetateDMF2-Propanol1-PropanolWater

triethylamine

heptane

Free energy of Hydration [kcal/mol] for Ions

-120

-110

-100

-90

-80

-70

-60

-50

-120 -110 -100 -90 -80 -70 -60 -50

Experiment

Cal

cula

ted

Ionic Free Energies of Hydrationby COSMOtherm-Ion-Extension

ln(gamma_inf) calc. / exp. (T=314/333K)in 4-methyl-n-butylpyridinium BF4

Lit: Andreas Heintz, Dmitry V. Kulikov, Sergey P. Verevkin, J. Chem. Eng. Data 2001, 46, 1526-1529

0

1

2

3

4

5

6

0 2 4 6exp.

CO

SMO

ther

m

non-aromaticcompoundsaromatic compounds

Applications of COSMOtherm to Ionic Liquids

log(Partition) for H2O / 1-butyl-3-methyl-imidazolium(+) - PF6(-)

-2.0

-1.0

0.0

1.0

2.0

3.0

4.0

-2.0 -1.0 0.0 1.0 2.0 3.0 4.0

COSMOtherm (pure prediction)

exp.: J.G. Huddleston,University of Alabama

COSMOtherm appears to work well for Ionic Liquids

COSMOtherm first principle pKa prediction ( A. Klamt, et. al. J. Phys. Chem. A, Nov. 2003)

pKa = 0.59∆ Gdiss/(RTln10) +0.88

N=60 R2=0.978, rms=0.49

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

0 10 20 30 40

∆ Gdiss

pKa_

exp

all

alcohols

carboxylic acids

inorganic acids

subst. phenols

N-acids (uracils,imines)Linear (all)

Uracil

and others

trans-5-formyluracilthyminecis-5-formyluracil5-nitrouracil5-fluorouracilboricacidphosphoricacid2sulfurousacidnitrousacidhypoiodousacidhypobromousacidhypochlorousacid2,2,2-trichloroethanolethanolpentachlorophenolphenolcarbonicacid0fumaricacidmaleicacid3oxalicacid0benzoicacid

2,2-dimethylpropanoicacidn-pentanoicacidtrichloroaceticaciddichloroaceticacid0chloroaceticacidaceticacidformicacid

latest results for bases (pKb):similar rmsslope between 0.59 and 0.71

σ-Moment Approach

>±+<±

≅=

≥=≅

−−

−=∑

hbhb

hbdonacc

ii

m

ii

iSS

ifif

ff

andiforfwithfc

σσσσσσ

σσ

σσσσµ

0)()(

0)()()(

/1/2

2

XsoluteofmomentsdfpMwith

Mcdfcpdp

iXX

i

m

i

Xi

iS

m

ii

iS

XS

XXS

−==

≅≅=

∫

∑∫ ∑∫−=−=

σσσσ

σσσσσµσµ

)()(

)()()()(22

Now the chemical potential of a solute X in this matrix S is:

The coefficients can now be derived from experimental (log.) partition databy linear regression. => σ-moments are excellent QSAR-descriptors forgeneral partition behaviour of molecules. “The solvent space is approximately 5-dimensional!“Zissimos, et al.: ‘A comparison between the two general sets of linear free energy descriptors of Abraham and Klamt‘, J. Chem. Inf. Comput. Sci., 42, 1320-1331 (2002) σ -moment models for ADME proprties as

logBB, intestinal absorption, logHSA, …

-0.70

-0.50

-0.30

-0.10

0.10

0.30

0.50

0.70

-0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.020

σ-po

tent

ial

WaterAcetoneHexane

σ -moment logBB regressionlogBB = 0.0046 area -0.017 sig2 -0.0029 sig3 +0.19

n = 103, r² = 0.71, rms = 0.40data from: "Modeling Blood-Brain Barrier Partitioning Using Topological Structure

Descriptors", Rose, Hall, Hall, and Kier, MDL-Whitepaper, 2003

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

calc.

exp.

minimum_COSMO_conf.CORINA_optimized

σ-moment logKHSA regressionlogKHSA = 0.0081 area -0.016 sig2 -0.013 sig3 +0.145 sigHacc+0.88n = 82, r² = 0.69, rms = 0.33data from: Kier, Hall, Hall, MDL-Whitepaper, 2002

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

logK(HSA) [calc.]

logK

(HSA

) [ex

p.]

0.008115997

0.008115997-0.016419311

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

PIA calculated by COSMO-KIA

PIA

exp

.

training set: n=38,rms=12.5%high quality test set: n=107,rms=12.8%questionable test set:n=24, rms=22%

COSMO-RS for Percentage Intestinal Absorption (PIA)Klamt, Diedenhofen, Connolly*, Jones* (submitted) *) GlaxoSmithKline

1.370.117M-0.113M-0.0024M-0.0053M-0.0040Mlog donacc320 +=KIA

-1

0

1

2

3

4

5

6

7

-1 0 1 2 3 4 5 6 7

COSMO-KOC

exp

. lo

gK

oc

Training Set rms=0.63

Test Set rms=0.72

Linear (Training Setrms=0.63)

Prediction of Soil SorptionJournal of Environmental Toxicology and Chemistry, in print

Adsorption to Activated Carbon

y = 0.9277x + 0.1379R2 = 0.9281

-10

-5

0

5

10

15

-10 -5 0 5 10 15

ln[He(exp.)]

ln[H

e(th

eor.)

]

Fluid Phase (23 Adsorptives)

Gasphase (15 Adsorptives)

Linear (Fluid Phase (23Adsorptives))

[Mehler, Peukert (TU München), Klamt; to be published]

solvent1

solvent2

solvent3

Free Energies relevant for Reactions

sum ofeducts

transitionstate (TS)

sum ofproducts

∆Greact

⇒equilibrium constant

∆Gactivation

⇒ kinetic constant

localisation of transition state often complicated: In this work gas-phase TS have been localised using techniques provided in Gaussian98 (DFT: B3LYP, 6-31G*)after that: single-point DFT/COSMO withTURBOMOLE (BP91-TZVP)

DFT is not reliable for TS energiesbut the solvent shifts should be reliable.

Calculation of the solvent dependence of ∆Greact is straightforward with COSMO-RS. Successful applications have been reported by industrial users (Dr. Franke, Degussa AG; Dr. Lohrenz, Bayer AG)

COSMOmic: Simulation of molecules in micelles and membranes

Concept:-define layers of membrane (shells of micelle)

-get probability to find a certain atom of surfactant in each layer (e.g. from MD)-convert this into a σ-profile p(σ,r) for each layer r using the COSMO-file of the surfactant-use COSMOtherm to calculate µ(σ,r) considering each layer as a liquid mixture-now calculate the chemical potential of a solute X in a certain postion and orientation by summing the chemical potentials of its segments in the respective layer. -sample the chemical potentials all positions and orientations of X

-construct a total partition sum and get the probability to find the solute in a certain depth and orientation.

-also get the average volume expansion in each layer- get a kind of micelle or membrane-water partition coefficient

o

o

o

o o

o

The tool COSMOmic facilitates all the previous steps together with COSMOthermPerspective: self-consistent treatment of new surfactants; CMC prediction

COSMOfrag: A fast shortcut of COSMOtherm suited for HTS-ADME prediction

1) large database of precalculated drug-like compounds (about 45000)2) for new compound find most similar fragments in database3) compose COSMO surface from surface fragments (write a meta-file)4) do usual COSMOtherm: solubility, partition properties

advantages: -about 1 sec. per compound!-you can add your typical inhouse structures to database -simple refinement of calculations

COSMOfrag ports COSMO-RS to Cheminformatics!

COSMOfrag:statistics and examples

Prediction of Soil Sorption Coefficients with COSMOfrag

0

1

2

3

4

5

6

0 1 2 3 4 5 6COSMOfrag

exp.

dat

a

Trainingsset rms=0.72 (0.63)

Tes tset rms=0.81(0.72) -10

-8

-6

-4

-2

0-10 -8 -6 -4 -2 0

log(xH2O) [meta]

log(

x H2O

) [ex

p.]

Water Solubility with COSMOfrag

Dataset of Jorgensen and Duffyrms: 0.71 (0.66)

Ligand – Recptor Binding

0

5

10

15

20

25

30

35

40

45

50

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

Retinal

Bacteriorhodopsinbinding pocket

σ−profiles of the binding pocket of bacteriorhodopsin and retinal

Retinal

Mouth of the Retinal binding pocket

Meanwhile we can approximately treat enzymes and receptor pockets.The goal is to describe ligand receptor binding (incl. desolvation) based

COSMO polarization cahrge densities σ.

COSMOsimbio-isoster search based on s-profilesexamples by Dr. M. Thormann, Morphochem AG

If the physiological distribution and the drug-receptor binding are governed by the COSMO σ-profiles, it is reasonable to use these for drug-similarity searching:

- search for molecules with maximum similarity of σ-profilesin order to find molecules with similar interactions, but different chemistry

-search is only based on surface polarity (σ) and not on structure

scaffold hopping

- either search over full COSMO-files of COSMOfrag-DB (48000 compounds)-screen millions of candidate compounds using the COSMOfrag method -Refine your search by explicit COSMO calculations on the most similar ~500 compds.

Lit: M. Thormann, A. Klamt, M. Hornig and M. Almstetter, "COSMOsim: Bioisosteric Similarity Based on COSMO-RS σ-Profiles”, J. Chem. Inf. Model. 46, (2006).

A.Bender, A. Klamt, K. Wichmann, M. Thormann, and R.C. Glen, „Molecular Similarity Searching Using COSMO Screening Charges (COSMO/3PP)“, in M.R. Berthold et al. (Eds.): CompLife 2005, LNBI 3695, pp. 175–185, 2005.Springer, Berlin Heidelberg 2005

Example 1: propionic acid

0.676719GXSEIQGKPCC1CC1C(=O)O

0.680418HLKLSJLHIOCCS

0.681717CUOCJIGKIOC(=O)C1CCC1

0.688516UMBRJEKLIOc1csnn1

0.691915HOMSZUGLICC(=O)C=NO

0.697814FFBMJKDKIOCCC(=O)O

0.698313EZHYEWAJICC(=NO)C

0.704112JMAKWZALIClc1nnn[nH]1

0.705211CZWYICCKICC(=O)O

0.710910WOJBMNDKVCC(O)C(=O)O

0.71719NBAKLRQLIOc1nnns1

0.72338HTYYARCJZCC(O)C#N

0.72697SDLNNSMIAOCC1CO1

0.74876DGWQYNDKICC(C)C(=O)O

0.75845VGZSDPDLICC=CC(=O)O

0.7654WCMTTAFLICC(=C)C(=O)O

0.7913RGQGEAHMICC=CC(=O)O

0.79962IAVMXKDKICCCC(=O)O

0.81691ITPZMBCLIOC(=O)C=C

10ZFQCMUCKICCC(=O)O propionic acid similars

-2

0

2

4

6

8

10

12

-0.03 -0.02 -0.02 -0.01 -0.01 0 0.01 0.01 0.02 0.02 0.03

p7p8p9p12p13p0p15

p7

p15p13p12

p9p8

Example 2: Metabotropic Glutamate Receptor Ligands

Synthesis and Pharmacology of Metabotropic Glutamate Receptor LigandsGrube-Jörgensen et al., ISMC 2004P239Drugs of the Future 2004 (29) Suppl. A: XVIIIth Symposium on MEDICINAL CHEMISTRY

A B C D a b c dA 1.000 0.711 0.666 0.697 0.396 0.440 0.459 0.488B 0.711 1.000 0.852 0.835 0.406 0.487 0.459 0.530C 0.666 0.852 1.000 0.857 0.378 0.461 0.455 0.507D 0.697 0.835 0.857 1.000 0.357 0.437 0.403 0.492a 0.396 0.406 0.378 0.357 1.000 0.665 0.679 0.642b 0.440 0.487 0.461 0.437 0.665 1.000 0.742 0.792c 0.459 0.459 0.455 0.403 0.679 0.742 1.000 0.700d 0.488 0.530 0.507 0.492 0.642 0.792 0.700 1.000

Tanimotoprime coefficients for COSMOsim matrixGlu (A), ibotenic acid (B), and thioibotenic acid (C) areknown mGluR agonists.D is novel and does also show mGluR agonist activity with mGluR subtype specificity most similar to that of C. The querie of d to our inhouse database containing > 2.000.000 sigma profiles employing the Tanimotoprime coefficient retrieves b at rank 3 with a similarity of 0.792.(M. Thormann, Morphochem, 2004)

0

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14

16

-0.02 -0.015 -0.01 -0.005 0 0.005 0.01 0.015 0.02

abcd

COSMO-RS: From Quantum Chemistry to Cheminformatics

• The quantum-chemically derived surface polarization charge densities σ provide a novel and very rich description of molecular interactions in liquids and pseudo-liquids phases, combing electrostatics, hydrogen bonding and “hydrophobic interactions“ in one picture.

• COSMO-RS provides a novel, extremely fast and efficient way to do thermodynamics based on σ-profiles.

• drug solubility and many important ADME properties can be calculated with COSMO-RS

• Quantum chemical DFT/COSMO calculations are reasonably feasible for a few hundred or thousand drug-like molecules.

• COSMOfrag derives approximate s-profiles for druglike compouds in a second.

• COSMOsim enables drug-similaity screening based on σ-profiles------------------------------------Outlook: Ligand recepor binding based on σ-profiles

gas phase

latitudes ofsolvation

water

acetone

alkanes

horizon ofCOSMO-RS

horizon of gas-phase methods

solid

statebridge ofsymmetry

Hope you enjoyed the trip to the latitudes of solvation!

QM/MMCar-Parrinello

-OH

-OCH3

-C(=O)H

-CarH-CarH -C

arH-Car

-Car -Car

Group contribution methodsUNIFAC, CLOGP, LOGKOW, etc.

Quantum Chemistrywith dielectric

solvation models like COSMO

or PCM

MD / MCsimulations

native home of computational chemistry

COSMO-RS

state of ideal screening home of COSMOlogic

For references see: www.cosmologic.de

or read my book (Elsevier, 2005)COSMO-RS: From Quantum Chemistry to

Fluid Phase Thermodynamics and Drug Design

We are looking for an excellent cheminforatics expert to join our

team!

COSMO-RS for Drug-Design and -Development• water solubility of drugs, • Solvent Screening: relative solubilities of drugs in various solvents and mixtures• partition behaviour between almost arbitrary phases (blood-brain, intestinal absorption, BCF, ...)•. pKa prediction• visualization of partition coefficients and solubility as surface properties• one descriptor (σ) for entire interactions - electrostatics

- hydrogen bonding- lipophilicity/hydrophobicity

=> useful property for MFA- chemical potential of crystal surfaces in solution (morphology of drugs)•.identification of binding sites from σ-hotspots• surface integral scoring function for docking, including desolvation - extension to membrane and micelle partitioning

------------------------------------COSMOfrag: σ-profiles built from similar fragments out of 30000 compound database brings COSMO-RS in to the range of 5 sec./compound => applicable to HTS

Ideas for drug drug-receptor binding with COSMOtherm

-we need the σ-profile of the receptor once (QM/MM? not yet solved)

- we simply have the σ-profile of the ligands (even from COSMOfrag)

Idea 1: generate scoring function from COSMO-RS surface interaction modelIdea 2: consider receptor pocket as a kind of pseudo-liquid (overestimated receptor flexibility, but may be interesting)

Both simply include desolvation

Sigma profiles of Enzymescalculated with linear-scaling AM1/COSMO

(MOZYME in MOPAC2002)

Some common features:• Large charge

distribution in the region around σ = 0.

• Carbonyl oxygen between 0.01 and 0.02.

• Charged side chains in the outer regions (σ<-0.02 andσ>0.02)

0

100

200

300

400

500

600

700

800

900

1000

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

BacteriorhodopsinBarnaseIsomeraseBPTICrambinPapainHIV-1 Protease

Bacteriorhodopsin and Retinal

0

5

10

15

20

25

30

35

40

45

50

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

Retinal

Bacteriorhodopsinbinding pocket

Sigma profiles of the binding pocket of bacteriorhodopsin and retinal

Retinal

Mouth of the Retinal binding pocket

A few shots of the binding pocket

Amino Acids: Sigma profiles on two computational levels

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-0.03 -0.02 -0.01 0 0.01 0.02 0.03

Alanine, AM1Alanine, BP/SVPGlutamic acid, AM1Glutamic acid, BP/SVPHistidine, AM1Histidine, BP/SVP

-COOH

-COOH

N lone pair

Alanine

Glutamicacid

Histidine