Course in Advanced Medicinal Chemistry (KEN760) Lecture Chalmers Technical University, Oct 2007

5. The Conceptual Union Between Chemistry and Biology goes back a long way ….

6. So does Bioactive Compound Structure Representation…..

7. But Times Have Changed …..

8. November 2004: The Seeds of Revolution

9. Strophanthidin: from 1952 to 2007: Now just a click to Hinxton… http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:38178

10. Or Bethesda…. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6185

16. The NIH Roadmap Chemical Diversity Technology Development Screening Instrumentation Assay Development Predictive ADMET Compound Repository (MLSMR) Informatics Chem- informatics Research Centers Molecular Libraries Screening Centers Network ( M L S C N )

18. Growth In PubChem Substances & Compounds Todays compound count: All: 10954831 BioAssay: 561883 Protein3D: 11717 Rule of 5: 7133978

19. GenBank PubChem

20. Top PubChem Depositors 56 current depositors 22 current depositors DiscoveryGate 4608994 ZINC 3813892 ChemDB 3564938 Thomson Pharma 2303628 ChemBridge 433971 ChemBank 413586 ChemIDplus 383789 Asinex 362469 DTP/NCI 268696 Specs 204658 DTP/NCI 173 NIH Chemical Genomics Center 60 Structural Genomics Consortium - Oxford 43 Scripps Research Institute 37 University of Pittsburg MLSC 33 Southern Research MLSC 29 San Diego Center for Chemical Genomics 22 BindingDB 20 Penn Center for Molecular Discovery 19 Emory MLSC; Vanderbilt MLSC 15

21. Growth In PubChem BioAssays Todays count: All: 637 Confirmatory: 250 MLSCN: 365 Protein Target: 257 Screening: 204 Summary: 1

23. Assay Example

24. Advanced Functionality

25. Bio-Chem Data Joins

26. The Biology Union

27. Entrez Connectivity Map

28. Expanding Relationships in Entrez Protein Sequences Literature PubMed VAST Structure Similarity Bioactivity Assay Results Small Molecule Structures Protein 3D Structures Biological Terms MeSH indexed 2D Chemical Structure Similarity (3D soon) Activity Profile Similarity Protein Sequence BLAST Sequence Similarity

29. A Pharmaceutical Portfolio from PubChem arixtra = CID 636380 factor Xa inhibitor odiparcil = CID 216385 thrombin inhibitor carvedilol = CID 2585 alpha/beta blocker levitra = CID 110634 PDE-5 inhibitor avodart = CID 152945 5-ARI inhibitor cutivate = CID 444036 anti-inflammatory hycamtin = CID 60699 topoisomerase inhibitor zofran = CID 4595 serotonin type 3 receptor antagonist avandir = CID 77998 PPAR gamma inhibitor seroxat = CID 5284605 SSRI wellbutrin = CID 62884 dopamine uptake blocker imigran = CID 5358 serotonin 5HT1 agonist lamictal = CID 3878 calcium channel blocker flixonase = CID 444036 anti-inflamatory serevent = CID 5152 adrenergic beta-agonist ariflo = CID 151170 PDE IV inhibitor SB 204070A= CID 121880 5-HT4 receptor antagonist SB-220453 = tonerbasat = CID 3055165 anticonvulsant

30. Joining to Protein Structure Cn3D view of PDB 1I7G on the left PubChem tesaglitazar=CID 208901 on the right Superimposed non-identical structural neighbours of 1I7G on the left with 90% similar neighbours of tesaglitazar=CID 208901 on the right.

32. Zebrafish Example

33. Public and Commercial Pathway Info

34. PubChem is now a Global Hub Including bioinformatic dbs with in-links ChemBank, chemical genomics 0.4 mill ChEBi, enzyme ligands 8K KEGG, drugs and metabolites 14K ZINC, ready-to-dock 3.8 mill MMDB, PDB ligands 55K ChemIDplus, NIH tox data 383K GPCR-Ligand Database Human Metabolite db 2K MEROPS protease inhibitors DrugBank, drugs and targets 4K P u b C h e m ChemSpider 20 million Nature Chemical Biology 0.8 K Drugs of the Future 3.4K LIPID MAPS, metabolism 8.8K

35. Relationships in Bioactive Chemical Space Protein Sequences metabolomes & natural products assay data drug-like cpds from literature & patents drugs chem genomics & sys biol probes

40. The DrugBank Data Extractor: Extensive Target-Cpd Joins

41. Linkage between Swiss-Prot - DrugBank - PubChem - MMDB see these marketed target links (411) (15728) = 181 (2501)

42. Commercial Products Complement Public Sources

44. PubChem and Commercial Target db Overlaps 7.27 mill 128K 1.49 mill PubChem GVKBIO 4,150 86,143 34,674 353,623 3,162 WOMBAT 1,013,848 6,825,265

49. 7-CHLORO-1-METHYL-5- PHENYL-2H-1,4- BENZODIAZEPIN-2-ONE SMILES strings: c1ccccc1 INChI=1/C6H6/c1-2-4-6-5-3-1/h1-6H Text Analysis Operations for Chemistry Documents: Backfilling from Patents and Papers Name  Structure Program language-free entities 6 6 0 0 0 0 0 0 0 0999 V2000 6.7092 5.6087 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 6.7076 4.5056 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6607 3.9551 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6160 4.5062 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 8.6121 5.6136 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6583 6.1591 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 0 0 0 2 3 1 0 0 0 0 3 4 2 0 0 0 0 4 5 1 0 0 0 0 5 6 2 0 0 0 0 6 1 1 0 0 0 0 M END Connection tables

51. Flexible Boolean Searching

52. Search result: 49 hits in 0.8 seconds

53. Integrated Visualization Tools

54. Integrated Analytical Data Management for Public Domain Data

55. Integrated Access to Open-Access Literature Text-based searching of over 50,000 Open Access Chemistry Articles

56. External Integrations - Google Search Across Google Using InChI string

57. External Integrations – Patents Reel Two Surechem Portal