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Publication Abstract from PubMed

Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of 10 picks compared to 1 out of 10 for the other approaches. From this result and other additional analyses, we conclude that FEP can be a useful approach to guide this type of medicinal chemistry optimization once it has been validated for the system under consideration.

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.,Kuhn B, Tichy M, Wang L, Robinson S, Martin RE, Kuglstatter A, Benz J, Giroud M, Schirmeister T, Abel R, Diederich F, Hert J J Med Chem. 2017 Mar 13. doi: 10.1021/acs.jmedchem.6b01881. PMID:28287264^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.