Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV‑2 Main Protease through Computer-Aided Drug Design

The COVID-19 pandemic
has highlighted a clear need to ensure rapid
and equitable global access to health interventions in preparation
for future coronavirus-driven pandemics. Here, we report the discovery
of highly potent noncovalent inhibitors of the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus
(pan-CoV) Mpro inhibition through computer-aided drug design. Virtual
screening led to the identification of a noncovalent hit compound
with a piperazine core. Structure-guided scaffold morphing provided
a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided
designs, with induced-fit of Met49/Met165 and Gln189, resulted in
the identification of highly potent compound 30, which
exhibits pan-CoV Mpro inhibition and cellular antiviral efficacy against
the SARS-CoV-2 omicron variant. The optimized lead compound 30 was characterized by in vitro ADME/Tox assays and in vivo
mouse pharmacokinetics. These findings suggest that compound 30 could be an addition to the repertoire of tools used to
support future pandemic preparedness.