In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis

Abstract

Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2-22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.

Keywords: ACE2, angiotensin converting enzyme 2; ADMET assay; ADMET, absorption, distribution, metabolism, excretion and toxicity; BBB, blood-brain barrier; BOILED, brain or intestinal estimated permeation method; COVID-19; COVID-19, corona virus disease 2019; E, envelope protein; FDA, food and drugs administration; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; HERG, human ether-a-go-go-related gene; LOAEL, oral rat chronic toxicity; M, membrane protein; MD simulations; MD, molecular dynamics; Molecular docking; N, nucleocapsid protein; NSPs, non-structural proteins; RdRp; RdRp, RNA dependent RNA polymerase; S, spike glycoprotein; SARS CoV-2; SARS CoV-2, severe acute respiratory syndrome 2; UTR, untranslated region; WHO, world health organization; pp1a/b, polyproteins; ssRNA, single stranded ribonucleic acid.