Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors

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.