Computation of Absolute Binding Free Energies for Noncovalent Inhibitors with SARS-CoV‑2 Main Protease

Accurate, routine calculation of absolute binding free
energies
(ABFEs) for protein–ligand complexes remains a key goal of
computer-aided drug design since it can enable screening and optimization
of drug candidates. For development and testing of related methods,
it is important to have high-quality datasets. To this end, from our
own experimental studies, we have selected a set of 16 inhibitors
of the SARS-CoV-2 main protease (Mpro) with structural
diversity and well-distributed BFEs covering a 5 kcal/mol range. There
is also minimal structural uncertainty since X-ray crystal structures
have been deposited for 12 of the compounds. For methods testing,
we report ABFE results from 2 μs molecular dynamics (MD) simulations
using free energy perturbation (FEP) theory. The correlation of experimental
and computed results is encouraging, with a Pearson’s r2 of 0.58 and a Kendall τ of 0.24. The
results indicate that current FEP-based ABFE calculations can be used
for identification of active compounds (hits). While their accuracy
for lead optimization is not yet sufficient, this activity remains
addressable in separate lead series by relative BFE calculations.