Modeling Chemical Reactions for Drug Discovery

/slides/dirname/filename.ppt© Gasteiger et al.C3

Modeling Chemical Reactions for Drug Discovery

Johann GasteigerComputer-Chemie-Centrum

Universität Erlangen-NürnbergD-91052 Erlangen

Germanyhttp://www2.ccc.uni-erlangen.de

/slides/Biochemical_Pathways/Folien/CCC/gcb00.ppt© Gasteiger et al.C3


Chemical Reactions and Drug Design• target identification

enzyme reactions• lead discovery and lead optimization

library synthesissynthetic accessibilitystability of compounds

• ADME-Toxmetabolism of drugs toxicity

J.Gasteiger, J.Comput.Aided Mol. Des., 2007, 21, 33-52


Modeling Chemical Reactions

- theoretical chemist:

quantum-mechanical calculations: time-consuming

- organic chemist:

concepts for rationalizing reaction mechanisms

⇒ quantify physicochemical effects⇒ learn from the data gained by chemists in the lab

/slides/Biochemical_Pathways/Folien/CCC/roche_2.ppt© Gasteiger et al.C3


Calculation of Chemical Effects

charge distributionJ. Gasteiger, M. Marsili, Tetrahedron 36, 3219 (1980)

inductive effectJ. Gasteiger, M. G. Hutchings, Tetrah. Lett. 24, 2541 (1983)

resonance effectJ. Gasteiger, H. Saller, Angew. Chem. Int. Ed. Engl. 24, 687 (1985)

polarizability effectJ. Gasteiger, M. G. Hutchings, J. Chem. Soc. Perkin 2, 559 (1984)

bond dissociation energyJ. Gasteiger, Comp. Chem. 2, 85 (1978)


• alcohols (286 cpds.)• aliphatic acids (1109 cpds.)• phenols (452 cpds.)• benzoic acids (341 cpds.)• aliphatic amines (409 cpds.)

Prediction of pKa ValueCompound Classes


Prediction of pKa valuesDescriptors Used

electronic effects

steric descriptor


A pKa Model for Phenols

n = 452, r2 = 0.81, s = 0.95

Qtot,O , αO, A(2D), qπ,O

carboxyoOOOOtota IqDAQpK −+++−−= 3.22.154)2(2.10.24.480.7 ,, πα

OH

H2O+ O- H3O++


A pKa Model for Phenols

n = 452R = 0.81σ = 0.95Rloo-cv = 0.80σloo-cv = 0.97

0 5 10 15

02

46

810

12

pKa (observed)

pKa (

pred

icte

d)

2

2


SYLVIA

estimation of synthetic accessibility


de novo design system• constructs a diverse set of novel potential leads from scratch

however, these have to be synthesized by medicinal chemists

estimate synthetic accessibility• ranks these structures according to ease of synthesis

Receptor Structure Based Drug Design


Estimation of Synthetic Accessibility

structure-based:• molecular graph complexity • ring complexity • stereochemical complexity

starting material-based:• similarity to starting materials

based on made bonds• based on presence of product reaction center substructures (RCSS) extracted from reaction databases


Synthetic Accessibility

simple complex

3.49

3.56

5.28

6.58


Analysis of Pharma Estimations

• dataset = 100 structures with known synthetic routes were collected from J. Med. Chem.

- wide variety in size and complexity

• request: estimate synthetic accessibility (1-easy,10-difficult)

correlation coefficients for the estimationsALTANA1 ALTANA2 ALTANA3 4SC JG Lilly

ALTANA1 — 0,75 0,77 0,63 0,84 0,74ALTANA2 — 0,78 0,37 0,73 0,74ALTANA3 — 0,47 0,82 0,75

4SC — 0,56 0,51JG — 0,81Lilly —


Comparison of Synthetic Accessibility Estimations

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10

Predicted Synthetic Accessibility

Lilly

human - human human - computer

correlation = 0.75 correlation = 0.74

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10

ALTANA-3

Lilly

K.Boda, T.Seidel, J.Gasteiger, J.Comp.Aid.Mol.Des., 2007, in press

SYLVIAGraphical user interface

novice userstrying out & playing around

Web servicesimple deployment to lab benches

Batch versioneasy integration intoexisting workflows

Availability (planned)β-version in mid-Junefinal version for ACS national meeting, Aug. 2007


RetroSynthesis Browser

design of organic syntheses


RetroSynthesis Browser

DB of reaction centers and transformations

full reactiontarget

NH NH

O

NH NH

ONH NH

O

O

SN N

O

NH

NH + +

+

NH NH

O

NH2 NH2

OS

+

DB of reactions(Theilheimer,

BioPath, ELN, etc.)

……

S C O

O

CS


Methoxatin (coenzyme PQQ)

NH

ONO

HO2CCO2H

CO2H

• coenzyme for redox catalysis discovered in 1979 in methylotrophic bacteria (methane and methanol oxidation)

• present in mammals: growth factor, tissue protective agent, vitamin

• eight published syntheses (8 to 13 steps)


Methoxatin: First Published Synthesis (10 Steps)

NH2

NO2

OMeO O

OMe

NHCO

NO2

OMeNHCO

NH2

OMe

NHCO

NH

OMe

N

Me

CO2Me

NHCO

NH

OMe

MeO2C

NH2

NH

OMe

MeO2CO

MeO2C CO2Me NH

OMe

MeO2C

NH

CO2Me

OH CO2Me

NH

OMe

MeO2C

N CO2Me

CO2Me NH

O

MeO2C

N CO2Me

CO2Me

O

NHMeO2C

N CO2Me

CO2Me

OOMeMeO

NH

ONO

HO2CCO2H

CO2H

HCOOAc, HCO2H H2, PtO2, EtOH, 65°C1. NaNO2, HCl2. KOH, MeOH/H2O, 0°C

95% 93%

HCO2H, 80°C

72%

HCl

acetone/H2O Δ

dry HCl

> 90%79%60%

(NH4)2Ce(NO3)6

CH3CN/H2O, 0°C

HC(OMe)3, TsOH

MeOH, Δ

1. 0.5 N K2CO3, 85°C

2. HCl, pH 2.5

92%

98%

80%

25°C 25°C

Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599-5600


Methoxatin: Oxydation Step (1)

• suggested synthesis:

• published reaction:

NH

ONO

HO2CCO2H

CO2H

NH

ONO

CO2H

CO2HCo(AcO)2, NaBr, HOAc, AIBN

O2, dichlorobenzene, 110°C, 9 hrs

92%

Yang, F.; Sun, J.; Zheng, R.; Qiu, W.; Tang, J.; He, M. A. Tetrahedron 2004, 60, 1225-1228


Methoxatin: Diels-Alder Step (2)



Genisson, V. B.; Nebois, P.; Domard, M.; Fillion, H. Chem. Pharm. Bull. 2000, 48, 893-894

NH

OO

NH

ONO

NN

+

NH

OO

MeO2CNH

ONO

MeO2C

NN

+

42%

THF

RT


Methoxatin: Oxydation Step (3)



Cai, P.; Snyder, J. K.; Chen, J.-C.; Fine, R.; Volicer, L. Tetrahedron Lett. 1990, 31, 969-972

NH

OH

NH

OO

NH

OH

NHCO2Et

NH

OO

NHCO2Et

90%

(C6H5SeO)2O


Methoxatin: Azadiene Formation (4)



Corey, E. J.; Pearce, H. L. J. Am. Chem. Soc. 1979, 101, 5841-5843

ONH2 N

NN

+

O NN

NH2 N

95%

+CF3COOH

Tol, Δ


Methoxatin: Suggested Synthesis with RSB (4 steps)

O

NH2 N

NH

OH

NH

OO

NH

ONO

HO2CCO2H

CO2H

NH

ONO

NN +

+

(1)

(2)

(3) (4)


Endogenous Metabolism

analysis of enzyme reactions



BioPath Database

molecules and reactions are stored with atomic resolution:- molecules as connection tables- reactions with reaction center marked

• 1,533 structures

• 2,175 reactions

•

/slides/Biochemical_Pathways/Folien/CCC/roche_2.ppt© Gasteiger et al.C3

M.Reitz, O.Sacher, A.Tarkhov, D.Trümbach, J.Gasteiger, Org. Biomol. Chem., 2004, 2, 3226-3237.


Web-based Retrieval System

• web-based graphical user interface

• various rapid search methods for chemical structures

• structure search• substructure search• similarity search• 3D substructure search• search by EC number,

compartment, species

• search by reaction center

C@ROL

C ompoundA ccess & R etrievalO n L ine system http://www.mol-net.com/databases


Biochemical Reactions

lycopene β-carotene

acetyl-CoA + acetoacetyl-CoA 2-hydroxy-3-methylglutaryl-CoA

2-ketoglutarate + CO2 oxalosuccinate

isopentenyl-PP + dimethylallyl-PP geranyl-PP

D-glyceraldehyde-3-P + dihydroxyacetone-P β-D-fructose-1,6-P2


Reaction Center Searchsearch for biochemical reactions making a

single C-C bond

110 hits

CCmake/break


C-C Bond Formation

lycopene β-carotene

acetyl-CoA + acetoacetyl-CoA 2-hydroxy-3-methylglutaryl-CoA

2-ketoglutarate + CO2 oxalosuccinate

isopentenyl-PP + dimethylallyl-PP geranyl-PP

D-glyceraldehyde-3-P + dihydroxyacetone-P β-D-fructose-1,6-P2

⇒ what are the similarities between these reactions ?

⇒ can we find new uses for an enzyme ?


• search for enzyme inhibitors

• search for similar enzymes

• search for alternative pathways

Applications

/© Gasteiger et al.C3


Energy Diagram of an Enzyme Catalyzed vs. Uncatalyzed Reaction

⇒ an enzyme must most tightly bind the transition state

⇒ inhibitors are transition states analogs


Reaction Catalyzed by AMP Deaminase(EC 3.5.4.6)

nucleophilic substitution (AE)

AMP + H20 → IMP +NH3

H H

N

N

N

N

P O O

O O

O

O

O

N

H H

HH

H H

N

N

N

N

P O O

O O

O

O

O

O

HHH H

H

H H

OH H N

H H

H

+ +


Reaction Catalyzed by AMP Deaminase(EC 3.5.4.6)

intermediateAMP IMP

H H

N

N

N

N

P O O

O O

O

O

O

N

H H

HH

H H

N

N

N

N

P O O

O O

O

O

O

O

HHH H

H

H H

N

N

N

N

P O O

O O

O

O

OHH

H H

HO N

H H

H H H

+H2O -NH3


coformycin

N

N

O O

O O

HHH H

Inhibitor of AMP Deaminase:R-coformycin

H H

H

N

N

O H

H

H


Superimpositions with Carbocyclic Coformycin

carb. cof. + AMP

rms=0.19Å

carb. cof. + intermediate

rms=0.13Å

carb. cof. + IMP

rms=0.20Å(# atoms = 16)

M.Reitz, A.von Homeyer, J.Gasteiger, J.Chem.Inf.Model., 2006, 46, 2333-2341


Metabolism of Xenobiotics

selectivity between cytochrome P450 isoforms


Metabolism by Cytochrome P450 Enzymes

• different isoforms (isoform specificity)• e.g. 2D6 vs. 3A4

• different reaction types (chemoselectivity)• e.g. N- vs. O-dealkylation

• different reaction sites (regioselectivity)• e.g. aromatic hydroxylation in m- vs. p-position

Prediction of Selectivities


Data Set of 3A4, 2D6, and 2C9 Substrates

Training set: 146 drugs, substrate for 3A4, 2D6 or 2C9*

*Manga, N. et al. SAR and QSAR in Env. Res. 2005, 16, 43-61.

Bufuralol Tramadol Felodipine

O OH

N

OOHN

NH

O

O

O

O

Cl

Cl


SVM Model

• Descriptor (242 components)• Automatic variable selection: 12 components

•2D-ACidentity(5), 2D-ACqπ(3), 2D-ACqπ(6), 2D-ACχπ(5), 2D-ACqσ(1), 2D-ACqσ(2), 2D-ACχσ(6), 3D-ACidentity([5.8-5.9[Å), nacid_groups, naliphatic_amino , nbasic_n , r3

PredictabilityTraining: 90.4%5-fold CV: 87.8%


Validation of the SVM Model

• Validation set: 233 substrates from the Metabolite database

• Predictability: 82.8%

L. Terfloth, B. Bienfait, J. Gasteiger, „Ligand-based Models for the IsoformSpecificity of Cytochrome P450 3A4, 2D6, and 2C9 Substrates.“ J. Chem.Inf. Model. In print.

ISOCYP Webservice

http://www.molecular-networks.com/online_services


Acknowledgements

Dr. Bruno BienfaitDr. Krisztina BodaMaria CamargoDr. Yongquan HanAngelika Hofmann Alexander von HomeyerDimitar HristozovDr. Thomas KleinöderJörg MarusczykDr. Eric Pellegrini

Martin ReitzDr. Lothar TerflothDr. Dušica VidovićDr. Jinhua ZhangDr. Qian-Nan Hu

Molecular NetworksDr. Oliver SacherDr. Achim Herwig

Synthesis Design and ReactionPrediction

SYLVIAEstimation of synthetic accessibility

RetroSynthesis BrowserBrowse a reaction database for similar reactions

Prediction of Metabolism

BioPathDatabase of biochemical pathways in endogenous metabolism

XENIADatabase of metabolic reactions for xenobiotics(drugs, agrochemicals)

MetaboGenGeneral of metabolites of xenobiotics

ISOCYPClassification of organic compounds into the major cytochromeP450 isoform that metabolizes it

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Modeling Chemical Reactions for Drug Discovery

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