Diversity & tractability revisited in collaborative small molecule phenotypic screening library design |
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| Affiliation: | 1. Computational & Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Computational & Structural Chemistry, Merck & Co., Inc., 77 Sumneytown Pike, West Point, PA 19486, USA;3. Applied Computing, Merck & Co., Inc, 630 Gateway Boulevard, South San Francisco, CA 94080, USA;4. Discovery Sample Management, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, NJ 07065, USA;5. Screening & Compound Profiling, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;6. Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People’s Republic of China;2. Institute for Innovative Drug Design and Evaluation, Henan University, Kaifeng 475004, People’s Republic of China;3. School of Pharmaceutical Sciences, Guangxi University of Chinese Medicine, Nanning 530001, People’s Republic of China;1. Advanced Materials Division, Mintek, 200 Malibongwe Drive, Randburg 2125, South Africa;2. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS 2050, South Africa;3. Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown 2193, South Africa;1. KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, 3000 Leuven, Belgium;2. Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA;3. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, 3000 Leuven, Belgium |
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| Abstract: | Identification of purposeful chemical matter on a broad range of drug targets is of high importance to the pharmaceutical industry. However, disease-relevant but more complex hit-finding plans require flexibility regarding the subset of the compounds that we screen. Herein we describe a strategy to design high-quality small molecule screening subsets of two different sizes to cope with a rapidly changing early discovery portfolio. The approach taken balances chemical tractability, chemical diversity and biological target coverage. Furthermore, using surveys, we actively involved chemists within our company in the selection process of the diversity decks to ensure current medicinal chemistry principles were incorporated. The chemist surveys revealed that not all published PAINS substructure alerts are considered productive by the medicinal chemistry community and in agreement with previously published results from other institutions, QED scores tracked quite well with chemists’ notions of chemical attractiveness. |
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| Keywords: | High throughput screening Lead discovery Multi-parameter optimization Substructure alerts Chemist survey |
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