Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this study, with the structure of the SARS-CoV-2 Mpro complexed with a non-covalent inhibitor, we performed molecular dynamics (MD) simulations to determine the conformation of the complex when single amino acid residue in the active site is mutated. As a model of amino acid mutation, we constructed mutant proteins with one residue in the active site mutated to alanine. This method is called virtual alanine scan. The results of the MD simulations showed that the conformation and configuration of the ligand was changed for mutants H163A and E166A, although the structure of the whole protein and of the catalytic dyad did not change significantly, suggesting that mutations in His163 and Glu166 may be linked to drug resistance.
【저자키워드】 COVID-19, severe acute respiratory syndrome coronavirus 2, main protease, Molecular dynamics simulation, drug resistance, virtual alanine scan, 【초록키워드】 SARS-CoV-2, coronavirus, Mutation, molecular dynamics, protease, severe acute respiratory syndrome Coronavirus, inhibitors, MD simulations, MD simulation, MPro, SARS-CoV-2 Mpro, drug target, therapeutic agents, drug resistance, mutant, molecular, respiratory, inhibitor, Amino acid, Ligand, active site, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, potential therapeutic agents, complex, residue, conformation, Alanine, catalytic dyad, Glu166, HIS163, configuration, mutant proteins, whole protein, amino acid residue, Effect, performed, significantly, determine, potential therapeutic agent, mutated, changed, mutant protein, the SARS-CoV-2, 【제목키워드】 coronavirus 2, Site,