In silico drug repurposing of penicillins to target main protease mpro of SARS-CoV-2

Background: SARS coronavirus-2 (SARS-CoV-2) infection causes Novel Coronavirus Disease (COVID-19). It is a respiratory tract infection and currently becoming pandemic worldwide affecting more than 50 lakh people. As of now, there is no treatment or vaccine developed for disease management. The main protease, Mpro in SARS-CoV-2 is a druggable target explored by many scientists. We targeted this with the well-known approach of drug repurposing by using computational tools. Methods: Schrödinger software was used for the study. Ligands were prepared from US-FDA drug-bank by importing it to Maestro graphical user interphase, optimised using LigPrep, and molecular geometry minimized using OPLS3e force-field. M^pro crystal structure 6LU7 was downloaded from PDB and optimised. Molecules were docked using CovDock module in Glide docking. Further, molecular dynamics simulations were carried out for 100 ns using Desmond module. Results: In docking and molecular interactions studies, penicillins emerged as hits with consistent binding pattern by forming hydrophilic, hydrophobic, electrostatic interactions. The molecular dynamics simulations confirmed the interactions. Phenoxymethylpenicillin and Carbenicillin were found to interact consistently and appeared to be the most promising. Conclusion: Usually, antibiotics are discouraged from using in the viral pandemic because of the development of resistance. Azithromycin was combined with hydroxychloroquine to treat COVID-19. Penicillins are less potent and first-line antibiotics for most of the bacterial infections. This study suggests Phenoxymethylpenicillin and Carbenicillin can be tried along with hydroxychloroquine. Further, this study shows the possible exploration by drug repurposing using computer-aided docking tools and the potential roles of beta-lactams in COVID-19.