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IImproved mproved VVirtual irtual SScreening creening
SStrategies and trategies and EEnrichment of nrichment of
FFocused ocused LLibraries in ibraries in AActive ctive
CCompoundsompounds
UUsing sing TTarget-arget-OOriented riented DDatabasesatabases
ChemAxon 2005 User Group MeetingChemAxon 2005 User Group MeetingMay 20th, Budapest, HungaryMay 20th, Budapest, Hungary
Our Business
To provide global solutions in Knowledge Management-based Drug Discovery
Meet the needs of pharmaceutical and biotech companies to integrate information and generate knowledge on drug discovery by providing:
Target class databases : GPCR, Ion Channel, Kinase, Protease, Nuclear Receptor…
Bio-pharmaceutical relevant databases: ADME/Drug-Drug Interactions, hERG
Therapeutic area databases : Cancer, Antipsychotics…
Build coherent Knowledge Management platform to structure pharmaceutical industry R&D information
Current Product Portfolio
AurSCOPE Databases Target Based
- GPCR- Ion Channel- hERG
Biopharmaceutical Topics- ADME/Drug-Drug Interactions
AurQUEST Web-based application for querying databases
AurSTORE Storage of propriety and third party data Thesaurus and Glossaries for structured data
Analysis Application AurTAG: Functional Annotation module
AurSCOPE Statistics
PublicationsPublicationsAnalyzedAnalyzed
ActivitiesActivities LigandsLigands Target Target ProteinsProteins
GPCRGPCR16000
patents and publications
500,000 106,000 2300
ADME/ADME/Drug-Drug Drug-Drug InteractionsInteractions 4000 pub 92900
8725parent
compound & metabolites
400
HERGHERG 450 pub 7750 1000
Ion Ion ChannelsChannels
4000 patents and
publications126000 34000 365
AurSCOPE GPCR
Exhaustively annotated database of GPCR target/Ligand Activity Data
All Major GPCR Targets represented Data collected from 370+ journals Historical data 1950’s to current Biological Activity data from
- Binding, In vivo, Second Messenger, Isolated Organ & other biological protocols
AurSCOPE GPCR Data Base Constitution
Out of 370 journals
GPCR Main Data Sources
0200400600800
10001200140016001800200022002400
JChem Tools Integration
Live demo…Live demo…
Representation & Chemical SpaceFingerprints calculation
Virtual ScreeningVirtual Screening2D-Chemical similarity
2D-Pharmacophore Similarity
N
O
N
NN
O
N
N
N
Peptides Peptides excludedexcluded
AurSCOPE GPCR
88 20988 209
Query moleculesQuery molecules
AurSCOPE GPCR AurSCOPE GPCR Virtual ScreeningVirtual Screening
StandardizerStandardizer
PMapperPMapperGenerateMDGenerateMD
JKlustorJKlustor
PMapperPMapperStandardizerStandardizer
ScreenMDScreenMD
GenerateMDGenerateMD
HitStatisticsHitStatistics
OptimizeMetricsOptimizeMetrics
Hits
JKlustorJKlustor
ChemAxon ToolsChemAxon Tools
NK1 ReceptorNK1 Receptor
Klebe Klebe et al. et al.
J. Med. Chem.J. Med. Chem. 2004, 2004, 4747, , 5381-5392.5381-5392.•Modeling of the receptorModeling of the receptor
•Virtual screening by dockingVirtual screening by docking
2
3
1
Screening Screening SStrategytrategy
Klebe setKlebe set
Expert setExpert set
Aureus setAureus set
Klebe Klebe QQuery uery MMoleculesolecules J. Med. Chem.J. Med. Chem. 2004, 2004, 4747, 5381-5392, 5381-5392
3
1
Screening Screening SStrategytrategy
Klebe setKlebe set
Expert setExpert set
Aureus setAureus set
2
Expert Query Expert Query MoleculesMolecules
J.C. Beaujouan, Collège de France, J.C. Beaujouan, Collège de France, INSERM U114INSERM U114
2
1
Screening StrategyScreening Strategy
Klebe setKlebe set
Expert setExpert set
Aureus setAureus set3
Aureus Query MoleculesAureus Query Molecules
N
O
N
O
O
O
N
N O
N
N
N
N
N
N
OO
O
N
NN
O
N
N
NH
(I)
H(I)
637 molecules
Less than 5nMLess than 5nM
Number of clusters = Number of clusters = 2525
Number of singletons = Number of singletons = 77
Some Aureus Query MoleculesSome Aureus Query Molecules
More chemical scaffolds
Enriching the chemical diversity of query set
Number of active NK-1 hits (Number of active NK-1 hits ( 100 nM)) vs vs similarity thresholdsimilarity threshold
0
100
200
300
400
500
600
700
0.90 0.85 0.80 0.75 0.70
Similarity Threshold
# A
ctiv
e H
its
PFPF
0
100
200
300
400
500
600
0.90 0.85 0.80 0.75 0.70
Similarity Threshold
# A
ctiv
e H
its
CFCF
Klebe set
Expert set
Aureus set
Activity Repartition (sim. threshold = 0.85 )Activity Repartition (sim. threshold = 0.85 )
High (Activity 100 nM)
Medium (100 nM Activity 1000 nM)
Low (Activity 1000 nM)
21%
13%
66%
KlebeKlebe
(144)
(46)
(28)
23%
12%
65%
ExpertExpert
(224)
(81)
(42) 12% 4%
84%
AureusAureus
(409)
(59)(20)
Higher percentage of active molecules with Aureus set
Sim = 0.90Sim = 0.90
254 138
8 1
CF PF
Sim = 0.80Sim = 0.80
470 449
49 34
CF PF
Sim = 0.70Sim = 0.70
688
812
340
1157
CF PF
Activity and number of hits vs used fingerprintsActivity and number of hits vs used fingerprints
NK1
Not NK1
Non tested NK1 as potential hits knowing their biological activity on other targets
Ideal similarity thresholds to consider for virtual screening of external databases
Tanimoto Similarity Threshold
Virtual Screening of Virtual Screening of
External Molecular External Molecular
DatabasesDatabases
Supplier URL 1 IBS (InterBioScreen) www.ibscreen.com 2 ChemStar www.chemstaronline.com 3 IF LAB (Life Chemicals, Inc.) www.iflab.kiev.ua 4 KO (Key Organics) www.keyorganics.ltd.uk 5 MDD (Molecular Design and Discovery) www.worldmolecules.com 6 Otava www.otava.com.ua 7 Peakdale www.peakdale.co.uk 8 Specs www.specs.net 9 Tocris www.tocris.com 10 TOSLab www.toslab.com 11 Vitas-M www.vitasmlab.com 12 ActiMol www.actimol.com 13 Biotechnology Corporation of America www.biotech-us.com 14 ChemDiv www.chemdiv.com 15 Florida Center - Heterocyclic Compounds http://ufark12.chem.ufl.edu 16 AMBINTER SARL www.ambinter.com 17 ASINEX www.asinex.com 18 Enamine www.enamine.net 19 MicroChemistry Ltd. www.mch.ru 20 MedChemLabs, Ltd. http://mosmedchemlabs.com 21 AnalytiCon Discovery www.ac-discovery.com 22 ChemExper www.chemexper.com 23 NCI http://nci.cambridgesoft.com 24 Aurora Fine Chemicals www.aurora-feinchemie.com 25 ACB Blocks www.acbblocks.com 26 ChemBridge www.chembridge.com 27 Maybridge www.maybridge.com 28 MDPI www.mdpi.org 29 MDSI (MicroSource Discovery Systems, Inc.) www.msdiscovery.com 30 NanoSyn (Nanoscale Combinatorial Synthesis) www.nanosyn.com 31 AMRI (Albany Molecular Research, Inc.) www.albmolecular.com 32 ASDI BioSciences www.asdibiosciences.com 33 A-Synthese-Biotech www.a-syntese-biotech.dk 34 ChemT&I www.chemti.com 35 CombiPure www.combipure.com 36 Exclusive Chemistry Ltd www.exchemistry.com 37 LaboTest www.labotest.com 38 Matrix Scientific www.matrixscientific.com 39 Polyphor www.polyphor.com 40 Princeton BioMolecular Research www.princetonbio.com 41 Rare Chemicals GmbH www.rarechem.de 43 SynChem www.synchem.com 44 TimTec www.timtec.com
2.000.000 2.000.000 moleculesmolecules
MolLib: Aureus External Molecular MolLib: Aureus External Molecular DatabaseDatabase
MolLib MolLib DatabaseDatabase
MolLibMolLib
AsinexChemBridgeChemDivChemStar…
AsinexChemBridgeChemDivChemStar…
"Drug-like" Filtering
MolLibMolLib
N
O
N
O
O
O
N
N O
N
N
N
N
N
N
OO
O
N
NN
O
N
N
NH
(I)
H(I)
Representation & Chemical SpaceMolecular descriptors & Fingerprints
N
OCH3N
CH3
12
O
O
CH3
29
O
N
N
N
H(I)
NN
O
O
N
N
O
O
N
N
N
OO
Virtual Screening1) 2D-Chemical Similarity
2) 2D-Pharmacophoric Similarity
"Query"Molecules
"Consensus"Molecule
N
O
N
NN
O
N
N
N
Hits
FocusedLibraries
AurQuest(Biological Activity)
Virtual Screening Virtual Screening Strategy of MolLibStrategy of MolLib
287 molecules 100 nM
287 molecules 100 nM
AurQAurQUESTUESTClusteringClustering
Jarvis-Patrick Algorithm (JChem)Similarity Threshold : 65%
Jan. 2005
12 clusters
1e-7
1e-7
1e-7
Application: new "Opioid Receptor Like" Application: new "Opioid Receptor Like" ligandsligands
AurQuest (Jan. 05), JChem clusters
NOP Query Molecules (NOP Query Molecules ( 100 nM)100 nM)
Tanimoto Similarity Tanimoto Similarity thresholdthreshold
JChemJChemCFCF
JChemJChemPFPF
# hits# hits
0.9 13 0
0.8 25 14
0.7 - 23
0.6 - -
Nociceptin ligands: Nociceptin ligands: ResultsResults
1 PF hit : K1 PF hit : Kii = 45 µM = 45 µM
1 CF hit : K1 CF hit : Kii = 297 nM = 297 nM
ConclusionConclusion
Successful integration of ChemAxon’s cheminformatics Successful integration of ChemAxon’s cheminformatics toolkit within Aureus Pharma’s knowledge management toolkit within Aureus Pharma’s knowledge management plateforme. plateforme.
Exploitation of AurSCOPE databases in virtual screening Exploitation of AurSCOPE databases in virtual screening strategies.strategies.
Rapid 2D similarity search using ChemAxon’s fingerprints Rapid 2D similarity search using ChemAxon’s fingerprints in combination with Aureus-Pharma’s diversity-improved in combination with Aureus-Pharma’s diversity-improved molecular sets.molecular sets.
