Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

Ancy Iruthayaraj, Sivanandam Magudeeswaran, Kumaradhas Poomani

10.26434/chemrxiv.12204668.v1

Research curated

Abstract

Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (Mpro) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (Mpro). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 Mpro. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of Mpro enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of Mpro and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This in silico study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 Mpro enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
PPL-100	MK-8122, TMB607
nsp9	replicase
Uridylate-specific endoribonuclease	NSP15, Non-structural protein 15, Nonstructural protein 15, NendoU, endoRNAse	rep, ORF1a-1b
Darinaparsin
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b

Related interactions

Target	Drug	Type	Result
RNA dependent RNA polymerase	Darinaparsin	Computational	positive
nsp9	Darinaparsin	Computational	positive
Uridylate-specific endoribonuclease	Darinaparsin	Computational	positive
3C-like protease	PPL-100	Computational	positive