Elucidation of Binding Features and Dissociation Pathways of Inhibitors and Modulators in SARS-CoV-2 Main Protease by Multiple Molecular Dynamics Simulations

COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (M(pro)) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of M(pro). In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in M(pro) using a dataset of 163 3D structures of M(pro)-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of M(pro) and will facilitate its rational drug design for COVID-19.