Ligand and Structure-Based In Silico Determination of the Most Promising SARS-CoV-2 nsp16-nsp10 2′-o-Methyltransferase Complex Inhibitors among 3009 FDA Approved Drugs

Abstract

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2'-<i>o</i>-methyltransferase (2'OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2'-<i>o</i>-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with <b>SAM</b> (<i>S</i>-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2'OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (<b>1187</b>), Calcium folinate (<b>1913</b>), Raltegravir (<b>1995</b>), Regadenoson (<b>2176</b>), Ertapenem (<b>2396</b>), Methylergometrine (<b>2532</b>), and Thiamine pyrophosphate hydrochloride (<b>2612</b>)). Out of the docked ligands, Ertapenem (<b>2396</b>) showed an ideal binding mode like that of the co-crystallized ligand (<b>SAM</b>). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, R_g, SASA, and H-bonding) have been conducted for the 2'OMTase-Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2'OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of -43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2'OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds.