Potential of NO donor furoxan as SARS-CoV-2 main protease (M) inhibitors: analysis.

The sharp spurt in positive cases of novel coronavirus-19 (SARS-CoV-2) worldwide has created a big threat to human. In view to expedite new drug leads for COVID-19, Main Proteases (M) of novel Coronavirus (SARS-CoV-2) has emerged as a crucial target for this virus. Nitric oxide (NO) inhibits the replication cycle of SARS-CoV. Inhalation of nitric oxide is used in the treatment of severe acute respiratory syndrome. Herein, we evaluated the phenyl furoxan, a well-known exogenous NO donor to identify the possible potent inhibitors through studies such as molecular docking as per target analysis for candidates bound to substrate binding pocket of SARS-COV-2 M. Molecular dynamics (MD) simulations of most stable docked complexes (M- and M-) helped to confirm the notable conformational stability of these docked complexes under dynamic state. Furthermore, Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations revealed energetic contributions of key residues of M in binding with potent furoxan derivatives , . In the present study to validate the molecular docking, MD simulation and MM-PBSA results, crystal structure of M bound to experimentally known inhibitor X77 was used as control and the obtained results are presented herein. We envisaged that spiro-isoquinolino-piperidine-furoxan moieties can be used as effective ligand for SARS-CoV-2 M inhibition due to the presence of key isoquinolino-piperidine skeleton with additional NO effect.Communicated by Ramaswamy H. Sarma.