The document discusses challenges in academic drug discovery, including differences in perspectives between biology and chemistry personnel on what constitutes a "good target". It also discusses factors that determine a target's "drugability" from chemical and biological viewpoints. Additionally, it examines how the choice of screening libraries and targets can impact success, and provides a formula for successful academic drug discovery emphasizing competent medicinal chemistry, screening facilities, and project management.

1. Academic drug discovery: the chemistry challenges of target choice and screening library selection Christopher A. Lipinski Scientific Advisor, Melior Discovery [email_address]

4. Historically few “innovator” targets / year 24 New Ligands in 8 Years Across Everybody

5. Non combichem innovator drugs

9. Biology and Chemoinformatics Biology approach Is this target druggable in chemistry?

14. MLR-1023 aka Tolimidone

15. Not all targets are equal in screening Reproduced with permission from “Targeting signal transduction with large combinatorial collections”, D. S. Auld, D. Diller, K. Ho, Drug Discovery Today, 2002, 7(24) 1206-13. Size of colored graphic = screening success at Pharmacopeia

16. Distribution Parameters for 7483 INN/USAN Drugs Define the 90% Limits Corresponding to Properties Unfavorable for Oral Drug Absorption.

20. Protein protein ligand garbage Lepourcelet, Maina; Chen, Ying-Nan P.; France, Dennis S.; Wang, Huisheng; Crews, Phillip; Petersen, Frank; Bruseo, Charles; Wood, Alexander W.; Shivdasani, Ramesh A. Small-molecule antagonists of the oncogenic Tcf/  -catenin protein complex. Cancer Cell (2004), 5(1), 91-102.

21. Protein protein ligand ABT-737 Bruncko, Milan; Oost, Thorsten K.; Belli, Barbara A.; Ding, Hong; Joseph, Mary K.; Kunzer, Aaron; Martineau, Darlene; McClellan, William J.; Mitten, Michael; Ng, Shi-Chung; Nimmer, Paul M.; Oltersdorf, Tilman; Park, Cheol-Min; Petros, Andrew M.; Shoemaker, Alexander R.; Song, Xiaohong; Wang, Xilu; Wendt, Michael D.; Zhang, Haichao; Fesik, Stephen W.; Rosenberg, Saul H.; Elmore, Steven W. Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL. Journal of Medicinal Chemistry (2007), 50(4), 641-662.

22. Nice chemistry: topology in DOS libraries

23. Bad chemistry: aggregation false positives in HTS assays Remove these types of compounds from any assays These looked good to PHARMACIA screeners

24. Chemistry “quality” and biology effort > 80% flawed compounds?

26. Incomprehensible “ Reality” depiction in chemistry is incomprehensible to biology / genomics and vice versa. Chemistry much closer to pathology than to biology / genomics. Graphical pattern recognition is the forte of chemists

27. Chemistry pattern recognition

33. Chemistry space, drug-like and tool-like December 16, 2004 Nature

34. Sparse activity in chemistry scaffold space Quest for the Rings. In Silico Exploration of Ring Universe to Identify Novel Bioactive Scaffolds, Ertl et al. J. Med Chem., (2006), 49(15), 4568-4573 .

35. Sparse oral activity in property space Global mapping of pharmacological space. Paolini et al., Nature Biotechnology (2006), 24(7), 805-815.

37. Achnowledgement The financial support of the Kosciuszko Foundation is gratefully acknowledged The Kosciuszko Foundation, An American Center for Polish Culture, Promoting Educational and Cultural Exchanges and Relations Between the United States and Poland since 1925.