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

Al-Sehemi, Abdullah G.; Pannipara, Mehboobali; Parulekar, Rishikesh S.; Patil, Omkar; Choudhari, Prafulla B.; Bhatia, M. S.; Zubaidha, P. K.; Tamboli, Yasinalli

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(pro)) 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 in silico studies such as molecular docking as per target analysis for candidates bound to substrate binding pocket of SARS-COV-2 M(pro). Molecular dynamics (MD) simulations of most stable docked complexes (M(pro)-22 and M(pro)-26) 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(pro) in binding with potent furoxan derivatives 22, 26. In the present study to validate the molecular docking, MD simulation and MM-PBSA results, crystal structure of M(pro) 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(pro) inhibition due to the presence of key isoquinolino-piperidine skeleton with additional NO effect. Communicated by Ramaswamy H. Sarma