W O M B A TW O M B A TWOrld of Molecular BioAcTivityWOrld of Molecular BioAcTivity

Tudor OpreaSunset Molecular Discovery LLChttp://www.sunsetmolecular.com

Daylight MUG 18Santa Fe, NM, 02/24/04Copyright © Tudor I. Oprea 2004. All rights reserved

http://www.sunsetmolecular.com/

W O M B A TW O M B A TWOrld of Molecular BioAcTivityWOrld of Molecular BioAcTivity

Axes: MW, LogP, LogSw

0.001 – 638%

6 – 843%

8 - 14.418%

Inactives/SingleDose 1%

Bioactivity DistributionBioactivity DistributionBy Target TypeBy Target Type

Receptors (56.2%)

0.0 – 633%

6 – 844%

8 - 14.422%

Inactives/SingleDose 1%

Proteins (4.8%)

0.0 – 643%

6 – 845%

8 - 14.411%

Inactives/SingleDose 0%

Enzymes (39%)

0.0 – 644%

6 – 841%

8 - 14.414%

Inactives/SingleDose 2%

• Enzymes tend to have a higher rate of inactives/low actives• Receptors tend to have more medium/high actives

Target Type DistributionTarget Type DistributionBy ActivityBy Activity

enzyme55%

protein1%

receptor44%

enzyme45%

protein5%

receptor49%

enzyme37%

protein5%

receptor58%

enzyme29%

protein3%

receptor68%

Inactives (1%) Low Act. (38%) Medium Act. (43%) High Act. (18%)

• Enzymes dominate the inactive/low activity bins• Receptors clearly dominate the medium/high activity bins

WOMBAT HistoryWOMBAT History• SADB5 (May 2002):

• Project funded initially by AstraZeneca• 21700 structures (includes duplicates)• 36738 activities on 324 targets• 837 papers indexed (JMC 1996-1999)• 39.56% Ki, 53.52% IC50• 5.54% D2 or EC50

• WOMBAT 2003.2 (September ‘03):• 53126 entries (47872 unique structures) 98662 activities on 506 unique

targets, plus 236 inactives, 7982 ‘smaller than’ & 159 ‘greater than’ values• 2143 papers (2148 series) indexed (JMC 1994-1999)• 35.5% Ki, 56.6% IC50, 4.85% D2 or EC50• literature coverage included BMCL (2002), QSAR (2000-2001)

R o m a n i a n A c a d e m yInstitute of Chemistry Timisoara

WOMBAT 2004.1WOMBAT 2004.1• 76,165 entries (68,543 unique SMILES) covering 3039 series (over 3000

papers) and ~143,000 activities on ~630 targets

• Activities now include inactives (635), < (8916), > (259), @ (578 – single dose)

• 37.1% Ki (& variations), 55.85% IC50 (& variations), 4.44% D2 or EC50, 0.9% Kb and Kd , 0.1% MIC, 0.04% ED50

• Biochem. Pharmacol. 2001 [partial coverage], Bioorg. Med. Chem. Lett. 2002 [1-24], Chembiochem 2002 [partial], Eur. J. Med. Chem. 2001 [partial], J. Amer. Chem. Soc. 1975,1992,1993 [partial], J. Healt. Sci. 2003 [partial], J. Med. Chem. 1991 [partial], 1992-2000 [complete], 2003 [partial], Quant. Struct.-Act. Relat. 1998-2000 [partial]

• Fully integrated FEDORA server (Metaphorics LLC)

• New features include SwissProt IDs for most Targets and links (via the DOI format for 1737 entries) to PDF files for all literature entries

http://www.sunsetmolecular.com/products/?id=4

http://www.sunsetmolecular.com/products/?id=4http://www.sunsetmolecular.com/products/?id=4

Activity Profile for WOMBAT 2004.1Activity Profile for WOMBAT 2004.1Target Class Compounds (a) PercentG-Protein Coupled Receptors 28973 38.04Nuclear Hormone Receptors 688 0.90Integrins 1772 2.33Ion Channels 9008 11.83Aspartyl Proteases 3351 4.40Serine Proteases 1459 1.92Kinases 2842 3.73Cysteine Proteases 704 0.92Phosphodiesterases 1689 2.22Oxidoreductases 2010 2.64Oxygenases 2829 3.71Transporters 2264 2.97Others 18576 24.39

(a) number of structures active at least once/target, % of total entries

References Are Stored SeparatelyReferences Are Stored Separately

WOMBAT Quality ControlWOMBAT Quality Control• Chirality: What chemists can interpret, computers are not always able (the

“above/below the plane” must be strictly enforced)Not machine-readable Machine-readable

• Missing/altered atoms/substituents – overall error rate above 9%• Incorrectly drawn or written structures (3.4%); incorrect molecular formula or

molecular weight (3.4%);• Unspecified binding position for substituents or ambiguous numbering scheme

for the heterocyclic backbone (0.91%);• Structures with the incorrect backbone (0.71%);• Incorrect generic names or chemical names (0.24%);• Incorrect biological activity (0.34%);• Incorrect references (0.2%).

N

NRO

N

NH2N

N

N

OH OH

NH2

N

N

NNO

OH OH

R

WOMBAT Quality Control…WOMBAT Quality Control…

JMC Errors… 1JMC Errors… 1Reference Published Structure Corrected Structure Comment

JMC 37-476 chart 1

N

O

O

O NO O

O

rolipram: incorrect N atom position

JMC 43-2217 chart 1

N

N

O

N

N

O

A-85380: incorrect ring size

-||- & JMC 36-2645

NN

O

O

O N

N

O

tropisetron: methyl group in plus

-||-

N

N N

O

N O O N

O

N

ON

O

DAU-6285: missing methoxy; N instead O

JMC 37-758 chart 1 N

N

O

O

N

OH

N3

N

N

O

O

N

O

N3

Ro-15-4513: methyl group missing

JMC 37-787 figure 1

N

S

O

SO

O

OO

NS

O

S

epalrestat: E/Z config: E instead Z

JMC Errors… 2JMC Errors… 2Reference Published Structure Corrected Structure Comment

JMC 35-1969 chart 1

OO

O

O

O

O NHH

O

N

O

O

O

O

O

HH

bicuculline: incorrect chirality; incorrect ring fusion

-||-

N+

OO

H

O

HO

N+

O O

H

N+O

N+OOO

OO

HH

(+)-tubocurarine: incorrect N atom position; substitution position

JMC 37-1769 chart 1

NO

O

F

Br

NO

O

F

Cl

haloperidol: Br instead of Cl

JMC 38-16 scheme 1

O

N

NO

N

N

NOO

divaplon: missing nitrogen atom

JMC 43-71 figure 2

N

NN N

Cl

Cl

N

NN N

Cl

triazolam: missing chlorine atom

JMC Errors… 3JMC Errors… 3Reference Published Structure Corrected Structure Comment

JMC 43-1793 N

S NN

N OO

OO

N

N

N

S NN

N OO

OOO

N

N

argatroban: missing double bonded oxygen atom; missing chirality

JMC 41-1943 chart 1

ON

ClO

N N

N

O

NN

N

LY-297524: completely different structures

JMC 41-4196 N

N

NS

O

F

N

N

NS

O

F

SB-203580: missing S=O double bond

JMC 38-3645 figure 1

N

N

N

N

tacrine: missing two double bonds

JMC 38-3094 figure 1

N

O

O

O

O

N

O

O

O

levonantradol: methyl instead hydroxy,methyl & plus an extra double bond

JMC Errors… 4JMC Errors… 4

JMC 35-4509 table II O N

Othp

NY

X

O N

O NY

X

40, 41: THP in plus

JMC 35-3858 table IV

N

NX

O

NNX

53/R2: imidazoyl instead imidazolyl

JMC 43-236 table 1

X

O

FFF

O

O

FF

F

OX

6b: incorrect substituent

-||- X

NO

O

OF

FF

NO

O

X

F

FF

9: double bonded O atom in plus

JMC 39-3636 table 1

X

X

28xiii/R3: pent-4-yl instead hept-4-yl; confirmed from chemical name

JMC 40-1049 table 6

N

OO

X NO

X

69/R: wrong substituent; confirmed from chemical name

Other Errors… Other Errors… SciFinderSciFinder

Me

Ph

HO 2C

NH

NH

O

NH

O

NH

OS

SNH O

H2N

O

R

SS

S

N NN

N

N

S S

OO

O

O

O

O

N

O

WOMBAT: RB-370

Registry Number: 187454-94-0

The correct structure has a 13-member ring

Other Errors… Merck IndexOther Errors… Merck Index

N

N

O

O

N

O

NO N

O

ON

O

"Carisoprodol"Merck Index 13th ed #1854

Carisoprodol - correct structureMerck Index 13th ed has correct name

F E D O R AF E D O R A

http://www.metaphorics.com

http://www.metaphorics.com/

WOMBAT@FEDORAWOMBAT@FEDORA

WOMBAT PatternsWOMBAT Patterns• Dave Weininger wrote a SMARTS generator starting from a SMILES that was

hand-picked by Vera Povolna to match a specific (not the maximum common) substructure for each WOMBAT series

• These SMARTS are intended to capture the unique biological profile for each series – on occasion 2 such SMARTS were defined; note that hydrogens are matched exactly as defined in the series

[CH3]-[OH0]-[cH0]:1:[cH1,cH0]:[cH0]:2-[CH2]-[NH0](-[NH0]=[CH0](-[cH0]:2:[cH1]:[cH1]:1)-[CH2]-[cH0]:3:[cH0](:[cH1]:[nH0]:[cH1]:[cH0]:3-[ClH0])-[ClH0])-[CH0,SH0,CH1]=[OH0]

[CH2]-[CH2]-[NH0](-[CH2]-[CH2])-[CH2]-[CH2]-[OH0,SH0]-[cH0]:1:[cH1]:[cH1]:[cH0](:[cH1] :[cH1]:1)-[CH1]-2-[CH1](-[CH0,CH2]-[OH0]-[cH0]:3:[cH1]:[cH0](:[cH1]:[cH1]:[cH0]-2:3)-[OH0,OH1])-[cH0]:4:[cH1]:[cH1]:[cH1]:[cH1]:[cH1]:4

[OH1]-[CH0](=[OH0])-[CH2]-[CH1,CH2]-[NH1]-[CH0](=[OH0])-[CH2]-[NH1,NH0]-[CH0] (=[OH0])-[CH2,CH1,NH0]-[CH2]-[CH2]-[cH0]:1:[nH0]:[cH0]:2-[NH1]-[CH2]-[CH2]-[CH2]-[cH0]:2:[cH1]:[cH1]:1

[OH1]-[CH0](=[OH0])-[CH2]-[CH1,CH2]-[NH1]-[CH0](=[OH0])-[CH2]-[NH0]-1-[CH0](-[CH1](-[CH2]-[CH2]-1)-[CH2]-[CH2]-[cH0]:2:[nH0]:[cH0]:3-[NH1]-[CH2]-[CH2]-[CH2]-[cH0]:3:[cH1]:[cH1]:2)=[OH0]

[NH2]-[CH2]-[CH2]-[CH2]-[NH1]-[CH2]-[CH2]-[CH2]-[CH2]-[NH1]-[CH2]-[CH2]-[CH2]-[NH1]-[CH0,SH0]=[OH0]

• Provides interesting associations in FEDORA

Increased MW does not Increased MW does not warrant higher activitywarrant higher activity

67210 structures 138401 activities

MW

Increased Increased LogPLogP does not does not warrant higher activitywarrant higher activity

ELogP

66824 structures 137766 activities

How Small Can Active Compounds Be?How Small Can Active Compounds Be?Binned ELogP

Less -3 -1 1 3 More

10

20

30

40

50

60

70

80

90N

+O

NH2O

CH3

CH3

CH3NH2OH

OH

O

O

OHO

OHNH2

H

H

NNH

NH2

NCH3N N NH

CH3CH3

CH3

N

NH2

PO

OHNH2 N

NO

CH3

N

CarbacholMW = 143LogP = -3.8IC50 = 8.2 (m)

DopamineMW = 153LogP = -1.0IC50 = 8.7 (D2)

LY-379268MW = 187LogP = -4.6EC50 = 8.6 (mGLU2)

NicotineMW = 162LogP = 1.2Ki = 9.0 (nACh)

MedetomidineMW = 200LogP = 3.8EC50 = 8.5 (α2)

HistamineMW = 111LogP = -0.7Ki = 8.2 (H3)

CGP-27492MW = 123LogP = -1.7IC50 = 8.6 (GABA-B)

L-670548MW = 179LogP = 0.77Ki = 9.7 (m1)

TacrineMW = 198LogP = 2.7IC50 = 8.2 (BChE)

192 unique structures 46 targets 252 activities ≤ 10 nMMW ≤ 200 amu176 are likely to be charged at pH 7.4

AcknowledgmentsAcknowledgments• Maria Mracec, Liliana Ostopovici, Ramona Rad, Alina

Bora, Ionela Olah, Marius Olah, Magdalena Banda (Timisoara Institute of Chemistry of the Romanian Academy) and TIO introduced data in WOMBAT

• Marius Olah wrote the database interfaces• Maria Mracec, Marius Olah and TIO did the keyword

characterization• Marius Olah, Maria Mracec, Cristian Bologa and TIO

performed structural error checking• Vera Povolna and David Weininger (Metaphorics) for

implementing WOMBAT@FEDORA

The contents of this talk are copyright © Tudor I. Oprea 2004. All rights reserved

http://www.eurohttp://www.euro--qsar2004.orgqsar2004.org

15th European Symposium on15th European Symposium onQuantitative StructureQuantitative Structure--ActivityActivity RelationshipsRelationshipsIstanbul / Turkey 05Istanbul / Turkey 05--10 September 200410 September 2004

EuroQSAR 2004

Chair:Chair: Prof. Dr. Prof. Dr. EsinEsin AKI ŞENERAKI ŞENERsener@pharmacy.ankara.edu.trsener@pharmacy.ankara.edu.trCoCo--Chair:Chair: Prof. Dr. Prof. Dr. İsmailİsmail YALÇINYALÇINyalcin@pharmacy.ankara.edu.tryalcin@pharmacy.ankara.edu.trAddress for Correspondence:Address for Correspondence:ArmoriaArmoria CongressCongressarmoria@euroarmoria@euro--qsar2004.orgqsar2004.org

http://www.euro-qsar2004.org/http://www.euro-qsar2004.org/

W O M B A TWOrld of Molecular BioAcTivityW O M B A TWOrld of Molecular BioAcTivityBioactivity DistributionBy Target TypeTarget Type DistributionBy ActivityWOMBAT HistoryWOMBAT 2004.1Activity Profile for WOMBAT 2004.1References Are Stored SeparatelyWOMBAT Quality ControlWOMBAT Quality Control…JMC Errors… 1JMC Errors… 2JMC Errors… 3JMC Errors… 4Other Errors… SciFinderOther Errors… Merck IndexF E D O R AWOMBAT@FEDORAWOMBAT PatternsIncreased MW does not warrant higher activityIncreased LogP does not warrant higher activityHow Small Can Active Compounds Be?Acknowledgments

/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputCondition () /PDFXRegistryName (http://www.color.org) /PDFXTrapped /Unknown

/Description >>> setdistillerparams> setpagedevice