Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

Abstract

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

“…Thus, SASA profiles signified the conformational changes that might have happened during the protein-ligand interactions. The results obtained were in agreement with the previous studies [62] , [63] . According to the MM-PBSA free energy calculated between RdRp and the ligands, the binding free energy (ΔG bind) of RdRp-Fidaxomicin (—334.2±16.7 kj/mol) was stronger than that of RdRp-Rifabutin (—326.5±13.6 kj/mol), which was in line with the results of docking and MD simulation.…”

“…12 ). Previous docking and simulation studies of RdRp with various inhibitors including natural compounds have showed similar amino acids that are in agreement with the findings of the present study [63] , [64] .

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“…The electrostatic interaction ( ΔE electrostatic ) was found to be almost neutralized by the polar desolvation energy ( ΔE polar solvation ) and hence the net electrostatic interactions was unfavourable to the binding affinities. Recent simulation studies on RdRp have reported similar interaction pattern with major van der Waal interactions [63] , [64] . The binding analysis of RdRp-Fidaxomicin revealed the total binding free energy contributed by individual amino acids such as ARG569, LYS500, LEU576, LYS577, LYS593, MET601, SER759, and ALA797 was remarkable during the complex formation ( Fig.…”

Epigallocatechin Gallate and Isoquercetin Synergize With Remdesivir to Reduce SARS-CoV-2 Replication In Vitro

“…As shown in Table 1, EGCG and Isoquercetin were effective to inhibit SARS-CoV-2 replication by 50% at 85.65 ± 6.45 mM and 23.99 ± 1.07 mM, respectively. Isoquercetin has already shown its effectiveness against Influenza and Ebola virus (16,50) and has been proposed for SARS-CoV-2 treatment (51,52). Although the EC 50 of EGCG was relatively high using this assay, it was previously described as effective to block infection of ancestral SARS-CoV-2 and UK-B.1.1.7, SA-B.1.351 and CA-B.1.429 variants, in vitro (53).…”

A Review on Herbal Secondary Metabolites Against COVID-19 Focusing on the Genetic Variants of SARS-CoV-2

“…In addition, a proof of concept was provided by a study by Kushwaha et al, showing the docking of key SARS-CoV-2 proteins to quercetin (51). Their findings revealed that quercetin is a capable drug molecule.…”