Drug repurposing for SARS-CoV-2 main protease: Molecular docking and molecular dynamics investigations

Abstract

The current novel corona virus illness (COVID-19) is a developing viral disease that was discovered in 2019. There is currently no viable therapeutic strategy for this illness management. Because traditional medication development and discovery has lagged behind the threat of emerging and re-emerging illnesses like Ebola, MERS-CoV, and, more recently, SARS-CoV-2. Drug developers began to consider drug repurposing (or repositioning) as a viable option to the more traditional drug development method. The goal of drug repurposing is to uncover new uses for an approved or investigational medicine that aren't related to its original use. The main benefits of this strategy are that there is less developmental risk and that it takes less time because the safety and pharmacologic requirements are met. The main protease (Mpro) of corona viruses is one of the well-studied and appealing therapeutic targets. As a result, the current research examines the molecular docking of Mpro (PDB ID: 5R81 ) conjugated repurposed drugs. 12,432 approved drugs were collected from ChEMBL and drugbank libraries, and docked separately into the receptor grid created on 5R81, using the three phases of molecular docking including high throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP). Based on docking scores and MM-GBSA binding free energy calculation, top three drugs (kanamycin, sulfinalol and carvedilol) were chosen for further analyses for molecular dynamic simulations.

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

“…The crystallographic structures of HDAC6 and Hsp90 with PDB IDs 6PYE and 3D0B, respectively, were retrieved from the protein data bank ( accessed on 25 May 2022). After that, with the Protein Preparation Wizard tool of Maestro [ 61 ], the two proteins’ structures were prepared for the upcoming procedures. Firstly, they underwent structural pre-processing where bond orders were assigned, absent hydrogen atoms were added, zero-order bonds to metals and disulfide bonds were created, incomplete side chains and loops were filled, water molecules beyond 5 Å were deleted, and het states were generated at 7 ± 2 pH via Epik tool.…”

“…[ 68 ]. The free binding energy of the receptor–ligand complexes is determined by the following equation: ∆E = E c − E R − E L where ∆E is the free binding energy, E c is the target/ligand complex energy, E R is the receptor energy, and E L is the ligand energy [ 61 ]. The solvation model was set to be VSGB and the force field was OPLS4.…”

Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

“…Here, we report a target-focused computer-aided drug repurposing campaign to detect new inhibitors of MPro, and the experimental validation of a small subset of the identified in silico hits. Noteworthy, whereas several similar efforts have been described in literature, in many (if not most) cases no experimental confirmation of the in silico hits has been reported (Eleftheriou et al, 2020;Llanos et al, 2021;Pinzi et al, 2021;Silva et al, 2021;Omer et al, 2022).…”

Drug repurposing against main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular docking, MM-GBSA calculations and molecular dynamics

“…Mpro SARS-CoV-2 is found in the regions 3264–3569 (containing 306 residues) of polyprotein pp1a and pp1ab [ 22 , 23 ]. The importance of Mpro is due to the cleavage of polypeptides together with papaine-like protease (PLpro) to form 11 pp1a and 5 pp1ab, which are used in viral replication [ 5 , 6 , 9 , 22 , 24 ]. Lopinavir and ritonavir are useful inhibitors of Mpro in the treatment of COVID-19 by binding to Thr24, Thr26 and Asn119 Mpro residues [ 6 , 9 ].…”

“…Drug repurposing is considered to be a fast and cost-effective process because long-term trials are not required to approve drug safety [ 12 , 24 , 25 ]. Three repurposing approaches are used, which can be a computational approach, an experimental approach or mixed approaches [ 25 ].…”