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ChemAxon 2005 User Group Meeting May 20th, Budapest, Hungary

I mproved V irtual S creening S trategies and E nrichment of F ocused L ibraries in A ctive C ompounds U sing T arget- O riented D atabases. ChemAxon 2005 User Group Meeting May 20th, Budapest, Hungary. Our Business.

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ChemAxon 2005 User Group Meeting May 20th, Budapest, Hungary

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  1. Improved Virtual Screening Strategies and Enrichment of Focused Libraries in Active CompoundsUsing Target-Oriented Databases ChemAxon 2005 User Group Meeting May 20th, Budapest, Hungary

  2. 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

  3. 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

  4. AurSCOPE Statistics

  5. 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

  6. AurSCOPE GPCR Data Base Constitution • Out of 370 journals

  7. JChem Tools Integration Live demo…

  8. Representation & Chemical Space Fingerprints calculation AurSCOPE GPCR Virtual Screening AurSCOPE GPCR Peptides excluded Standardizer 88 209 PMapper GenerateMD Virtual Screening 2D-Chemical similarity 2D-Pharmacophore Similarity Query molecules JKlustor

  9. ChemAxon Tools Standardizer PMapper GenerateMD ScreenMD HitStatistics OptimizeMetrics Hits JKlustor

  10. Klebe et al. • J. Med. Chem. 2004, 47, 5381-5392. • Modeling of the receptor • Virtual screening by docking NK1 Receptor

  11. Screening Strategy Klebe set 1 2 Expert set 3 Aureus set

  12. Klebe Query Molecules J. Med. Chem. 2004, 47, 5381-5392

  13. Screening Strategy Klebe set 1 Expert set 2 3 Aureus set

  14. Expert Query Molecules J.C. Beaujouan, Collège de France, INSERM U114

  15. Screening Strategy Klebe set 1 2 Expert set Aureus set 3

  16. Aureus Query Molecules 637 molecules Less than 5nM Number of clusters = 25 Number of singletons = 7

  17. Some Aureus Query Molecules More chemical scaffolds Enriching the chemical diversity of query set

  18. Klebe set Expert set Aureus set Number of active NK-1 hits ( 100 nM)vs similarity threshold CF PF

  19. Klebe Expert Aureus (20) (28) (42) (59) (46) (81) (409) (144) (224) High (Activity  100 nM) Medium (100 nM  Activity  1000 nM) Low (Activity  1000 nM) Activity Repartition (sim. threshold = 0.85 ) Higher percentage of active molecules with Aureus set

  20. Sim = 0.90 Sim = 0.80 Sim = 0.70 1 8 34 49 340 1157 138 254 449 470 688 812 CF PF CF PF CF PF Activity and number of hits vs used fingerprints Tanimoto Similarity Threshold 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

  21. Virtual Screening of External Molecular Databases

  22. MolLib: Aureus External Molecular Database  2.000.000 molecules

  23. MolLib Database

  24. Representation & Chemical Space Molecular descriptors & Fingerprints Virtual Screening 1) 2D-Chemical Similarity 2) 2D-Pharmacophoric Similarity "Query" Molecules "Consensus" Molecule Virtual Screening Strategy of MolLib Asinex ChemBridge ChemDiv ChemStar … MolLib "Drug-like" Filtering AurQuest (Biological Activity) MolLib Focused Libraries Hits

  25. Application: new "Opioid Receptor Like" ligands 287 molecules  100 nM AurQUEST Clustering Jarvis-Patrick Algorithm (JChem) Similarity Threshold : 65% Jan. 2005 1e-7 1e-7 1e-7 12 clusters

  26. NOP Query Molecules ( 100 nM) AurQuest (Jan. 05), JChem clusters

  27. Nociceptin ligands: Results 1 PF hit : Ki = 45 µM 1 CF hit : Ki = 297 nM

  28. Conclusion • Successful integration of ChemAxon’s cheminformatics toolkit within Aureus Pharma’s knowledge management plateforme. • Exploitation of AurSCOPE databases in virtual screening strategies. • Rapid 2D similarity search using ChemAxon’s fingerprints in combination with Aureus-Pharma’s diversity-improved molecular sets.

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