Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A
Medicinal Chemistry approach.
Abstract
The global pandemic caused by a single-stranded RNA (ssRNA) virus known
as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is
still at its peak, with new cases being reported daily. Though the
vaccinations are done on a massive scale, the frequent mutations in the
viral gene and resilience of the future strains could be more
problematic. Therefore, there is always a need for new compounds to be
available for therapeutic studies. We carried out the present research
to discover potential drug compounds against the SARS-CoV-2 main
protease. A total of 16,000 drug-like small molecules from the
ChemBridge database were virtually screened to obtain the top hits. As a
result, 1032 hits were selected based on their docking scores. Next,
these structures were prepared for molecular docking, and each small
molecule was docked into the active site of the Mpro. Only those
compounds with strong interactions with the active site residues and had
the highest docking score were subjected to molecular dynamics (MD)
simulation. The post-simulation analyses were carried out using the
in-built GROMACS commands to gauge the stability, flexibility, and
compactness. Principal component analysis (PCA) and hydrogen bonding
were also calculated to observe trends and affinity of the drugs towards
the target. Among the five top compounds, C1, C3, and C4 revealed strong
interaction with the target’s active site and remained highly stable
throughout the simulation. We believe the predicted compounds in this
study could be potential inhibitors in the natural system and must be
considered for further practice.