Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits.
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.
Bayer HealthCare, Pharma Research & Development, Medicinal Chemistry, D-42096 Wuppertal, Germany.
Tobias
T
Wunberg
Martin
M
Hendrix
Alexander
A
Hillisch
Mario
M
Lobell
Heinrich
H
Meier
Carsten
C
Schmeck
Hanno
H
Wild
Berthold
B
Hinzen
D000284:Administration, Oral; D015195:Drug Design; D010599:Pharmacokinetics; D014116:Toxicology