Development of Multi-Target Pharmacophore-Based Virtual Screening Agent Against COVID-19

Abstract

Abstract The worldwide outbreak of the COVID-19 pandemic compelled scientists to develop new, highly effective therapeutic approaches to fight it. Multitarget drugs have been proven to be effective in managing complex disorders. But designing multitarget drugs is a great challenge. In this study, to prevent lack of efficacy due to viral mutation escape, a multi-target agent against the COVID-19 virus was discovered. As crucial targets, RNA-dependent RNA polymerase (RdRp), COVID-19 main protease (Mpro), and SARS-CoV-2 Nsp15 were selected. A pharmacophore model was developed using the native ligands of the chosen targets. This model was used to screen the ZINC Drug Database for commercially available compounds having similar features to the experimentally tested drugs. Pharmacophore-based virtual screening yielded 1331 hits, which were further docked into the binding sites of selected proteins using PyRx AutoDock Vina. Evaluation of docking results revealed that glisoxepide (Zn 00537804) has the highest binding scores for the three target proteins. It showed binding free energies of -6.8, -6.2, and -7.8 kcal/mol towards SARS-CoV-2 Mpro, Nsp15, and RdRp, respectively. According to an in silicoADME study, glisoxepide follows Lipinski's rule. The results of a molecular dynamics simulation study and subsequent investigations showed that glisoxepide had good dynamics and stability within the active sites of selected targets. The promise of glisoxepide as a potential treatment for SARS-CoV-2 still needs to be further evaluated through experimental research.