In Silico Drug Repurposing of Penicillins to Target Main Protease M^pro of SARS-CoV-2

Abstract

Background: SARS coronavirus-2 (SARS-CoV-2) infection causes Novel Coronavirus Disease . 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, M pro 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.

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment

“…Sahu et al 2020, have worked by taking SARS-CoV-2 3CL pro as a drug target in COVID-19 [10]. In our earlier attempts we found out that penicillin's had the potential to bind to M pro consistently, while phenoxymethylpenicillin and carbenicillin had high potential to act as an anti-COVID-19 agent which can be used alongside with anti-viral agents [11]. In another study, we repurposed USFDA approved drugs like aprepitant, barnidipine, tipiracil, arbutin and terbutaline by determining their binding ability to M pro there by acting an anti-COVID-19 agents [12].…”

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“…Ligprep in Schrodinger is used for pre-processing of ligands before performing extra precision docking with target proteins 33 . LigPrep in Schrodinger software optimizes ligands prepared from US-FDA drugbank for molecular interactions and drug repurposing 34 . Ligprep in Schrodinger is a module that prepares approved drugs for virtual screening and molecular dynamics simulations 35 .…”

A Molecular Modeling and Molecular Dynamics Simulations Investigation of the Potential Therapeutic Applications of Main Protease Inhibitors for SARS-CoV-2

“…The present pandemic has brought into sharper focus the critical need for improved readiness for and response to outbreaks of new infectious illnesses in the future. To battle emerging viruses, the scientific community should keep collaborating to provide fresh treatments and vaccinations (139). The ongoing research and development of antiviral drugs and vaccines for COVID-19 and other coronaviruses will also provide a foundation for responding to future outbreaks of other emerging infectious diseases (140).…”