Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

Abstract

The importance of the main protease (M pro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces M pro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 M pro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of M pro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of M pro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

Can Antiviral Activity of Licorice Help Fight COVID-19 Infection?

“…Several in silico docking studies suggested a direct interaction of GR and GA to these key players in virus internalization and replication: ACE2 [61][62][63], spike protein and its RBD [63][64][65][66], and 3CLPro [63,65,[67][68][69][70][71][72][73][74]. Only a few in silico analyses were negative (3CLpro [68,75], Spike [76]).…”

“…The main protease 3CLpro contains several canonical binding pockets, denoted P1-P4, in its active site [77]. In silico studies suggest the binding of GR to these pockets [63,[67][68][69][70][71][72][73][74]. However, when tested on enzyme activity, the results were contradictory.…”

Structure Guided Drug Designing Coupled to Advanced Molecular Dynamics Revealed Differential Binding Properties (Affinity/Stability) of Celecoxib and Niflumic Acid in the Active Site of Cyclooxygenase-2 Enzyme

“…Constant pressure, temperature and number of atoms were kept all through simulation. While pressure was kept 1.0 bar, temperature was maintained at 300 K using the proper algorithms [32,33]. However, before initiating molecular dynamics the systems were minimized as per standard guidelines.…”

“…While a exible ligand can alter its conformation on binding the target site in a best possible manner, the protein can change its dynamics and conformation for promoting ligand binding [35]. Thus it is obvious that static approaches like molecular docking should be coupled to dynamic approaches like molecular dynamics simulations for gaining more insights about ligand-receptor stability [28,32]. We subjected celecoxib-COX-2 complex and ni umic acid-COX-2 for 10 ns simulation using the Desmond software.…”

Molecular interactions and inhibition of the SARS‐CoV‐2 main protease by a thiadiazolidinone derivative

“… 20 Other compounds have been repurposed and tested on M Pro as well. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 …”