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Promiscuous patterns and perils in PubChem and the MLSCN
- 1. Promiscuous patterns and perils in PubChem and the MLSCN Jeremy J Yang Cristian Bologa Tudor Oprea Division of Biocomputing Dept of Biochem. & Mol. Biology NM Mol. Libraries Screening Center University of New Mexico
- 14. MLSMR re-filtered... Example rejects:
- 15. Pre-filtering at UNM Java servlet using ChemAxon/JChem
- 16. Activity multiplicity – all assays compounds active in any assay peril? 103894 MLSCN compounds 724 MLSCN assays
- 17. Activity multiplicity – screening assays compounds active in any screening assay peril 89954 MLSCN compounds 268 MLSCN assays
- 18. Top 100 hier-scaffolds*, active PubChem MLSMR Example scaffold #1 *Wilkins, J. Med Chem 2005
- 19. Top active hier-scaffolds: example #1 Scaffold: 33 rd most common 510 active compounds 34 assays c1c2c([nH]c(=O)cn2)ncn1 Top 12 compounds Top 12 of 510 compounds CID, #assays active
- 20. Top active hier-scaffolds: example #1 #compounds vs #assays in which they are active
- 21. Top active hier-scaffolds: example #1 All from NCGC
- 22. Other promiscuous scaffolds COMPOUNDS:total/tested/active ASSAYS:tested/active SAMPLES:tested/active
- 23. Other promiscuous scaffolds COMPOUNDS:total/tested/active ASSAYS:tested/active SAMPLES:tested/active
- 24. Other promiscuous scaffolds COMPOUNDS:total/tested/active ASSAYS:tested/active SAMPLES:tested/active
- 25. Activity mining with PubChem GUI Lots of great functionality, but not everything...
- 26. Activity mining with command line Automation is good...
- 27. Example scaffold #2 62 nd most common 523 active compounds 208 assays c1ccc(cc1)NC(=O)c2ccco2 Top active hier-scaffolds: example #2 Top 12 of 523 compounds CID, #assays active
- 28. Top active hier-scaffolds: example #2 #compounds vs #assays in which they are active
- 29. Top active hier-scaffolds: example #2 #compounds vs #assays in which they are active
- 30. Top active hier-scaffolds: example #3 Example scaffold #4 1307 th most common 27 active compounds 140 assays c1nc-2c(=O)[nH]c(=O)nc2[nH]n1 toxoflavin
- 31. Top active hier-scaffolds: example #3 #compounds vs #assays in which they are active
- 32. Digression: PubChem bug... substructure search for CID 66541 143 hits substructure search for C2(C1=NC=NNC1=NC(N2)=O)=O 143 hits substructure search for c1nc-2c(=O)[nH]c(=O)nc2[nH]n1 0 hits Ergo: aromatic structural queries not allowed?
- 33. Top active hier-scaffolds: example #3
- 34. More example scaffolds and histograms of #compounds vs. #assays in which compounds are active
- 39. Now for some general comments... 10 6 10 0
- 40. Probability – in HTS game etc. In other words: Quantity vs. Quality E not striking out = 1 – E striking out E success = 1 – (1 - E hit ) N where E hit = probability of hit per try N = number of tries
- 42. Probability, more quantity vs quality “ Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries”, Inglese et al., PNAS, 103, 2006, 11473-11478.
- 43. Probability and prejudice Lucky CEOs, coaches, and fund managers, Kahneman's 2002 Nobel prize for economics-psychology, good stories vs. Occam's razor, confirmation bias, pathological pattern-recognizers are we.
- 44. Statistics and signficance “ The Trouble with QSAR (or How I Learned To Stop Worrying and Embrace Fallacy)”, Stephen R. Johnson, J. Chem. Inf. Model., 48 (1), 25 -26, 2008.
- 50. HierScaffolds: - scaffolds are one or several rings connected by linkers - compounds can be related by any of their scaffolds