posted on 2021-08-30, 18:36authored byVinícius Bonatto, Anwar Shamim, Fernanda dos R. Rocho, Andrei Leitão, F. Javier Luque, Jerônimo Lameira, Carlos A. Montanari
Covalent inhibitors are assuming
central importance in drug
discovery projects, especially in this pandemic scenario. Many research
groups have focused their attention on inhibiting viral proteases
or human proteases such as cathepsin L (hCatL). The inhibition of
these critical enzymes may impair viral replication. However, molecular
modeling of covalent ligands is challenging since covalent and noncovalent
ligand-bound states must be considered in the binding process. In
this work, we evaluated the suitability of free energy perturbation
(FEP) calculations as a tool for predicting the binding affinity of
reversible covalent inhibitors of hCatL. Our strategy relies on the
relative free energy calculated for both covalent and noncovalent
complexes and the free energy changes have been compared with experimental
data for eight nitrile-based inhibitors, including three new inhibitors
of hCatL. Our results demonstrate that the covalent complex can be
employed to properly rank the inhibitors. Nevertheless, a comparison
of the free energy changes in both noncovalent and covalent states
is valuable to interpret the effect triggered by the formation of
the covalent bond on the interactions played by functional groups
distant from the warhead. Overall, FEP can be employed as a powerful
predictor tool in developing and understanding the activity of reversible
covalent inhibitors.