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Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits.

Wunberg T, Hendrix M, Hillisch A, Lobell M, Meier H, Schmeck C, Wild H, Hinzen B

Bayer HealthCare, Pharma Research & Development, Medicinal Chemistry, D-42096 Wuppertal, Germany.

Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME-Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME-Tox) is the distinctive feature that will define the priority for follow-up.

Published 14 March 2006 in Drug Discov Today, 11(3): 175-80.
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