Abstract
Since its emergence in early 2019, the respiratory infectious virus, SARS-CoV-2, has ravaged the health of millions of people globally and has affected almost every sphere of life. Many efforts are being made to combat the COVID-19 pandemic’s emerging and recurrent waves caused by its evolving and more infectious variants. As a result, novel and unexpected targets for SARS-CoV-2 have been considered for drug discovery. 2′-O-Methyltransferase (nsp10/nsp16) is a significant and appealing target in the SARS-CoV-2 life cycle because it protects viral RNA from the host degradative enzymes via a cap formation process. In this work, we propose prospective allosteric inhibitors that target the allosteric site, SARS-CoV-2 MTase. Four drug libraries containing ~119,483 compounds were screened against the allosteric site of SARS-CoV-2 MTase identified in our research. The identified best compounds exhibited robust molecular interactions and alloscore-score rankings with the allosteric site of SARS-CoV-2 MTase. Moreover, to further assess the dynamic stability of these compounds (CHEMBL2229121, ZINC000009464451, SPECS AK-91811684151, NCI-ID = 715319), a 100 ns molecular dynamics simulation, along with its holo-form, was performed to provide insights on the dynamic nature of these allosteric inhibitors at the allosteric site of the SARS-CoV-2 MTase. Additionally, investigations of MM-GBSA binding free energies revealed a good perspective for these allosteric inhibitor-enzyme complexes, indicating their robust antagonistic action on SARS-CoV-2 (nsp10/nsp16) methyltransferase. We conclude that these allosteric repressive agents should be further evaluated through investigational assessments in order to combat the proliferation of SARS-CoV-2.
Keywords: COVID-19; allosteric site; inhibitors; methyl transferase; molecular docking; simulation.
【저자키워드】 COVID-19, molecular docking, allosteric site, inhibitors, Simulation., methyl transferase, 【초록키워드】 SARS-CoV-2, Drug discovery, COVID-19 pandemic, molecular docking, molecular dynamics, binding free energy, inhibitors, variants, Molecular dynamics simulation, Simulation, Health, stability, methyltransferase, Research, target, Viral RNA, molecular, assessment, inhibitor, Infectious virus, proliferation, life, life cycle, Complexes, SARS-CoV-2 life cycle, enzyme, Perspective, Compound, effort, these compounds, molecular interaction, drug library, antagonistic action, Host, robust, PROTECT, affected, caused, evaluated, was performed, screened, exhibited, these compound, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, inhibition, identification, Site,