Identification and Inhibition of the Druggable Allosteric Site of SARS-CoV-2 NSP10/NSP16 Methyltransferase through Computational Approaches

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 16; p. 5241
• Main Authors: Faisal, Shah, Badshah, Syed Lal, Kubra, Bibi, Sharaf, Mohamed, Emwas, Abdul-Hamid, Jaremko, Mariusz, Abdalla, Mohnad
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-08-2022; MDPI
• Subjects: Algorithms; Allosteric properties; allosteric site; Cap formation; Computer applications; COVID-19; Crystallography; Drug discovery; Dynamic stability; Enzymes; Epidemics; Health aspects; Identification; Inhibitors; Kinases; Libraries; Ligands; methyl transferase; Methyltransferase; molecular docking; Molecular dynamics; Molecular interactions; Proteins; Research methodology; RNA; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Simulation; Stability analysis; Transferases; Viruses
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27165241

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.