Journal Article

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein

Rosita, Arokiaraj Sherlin, Selvaraj, Jayaraman, Manjunathan, Reji, Doble, Mukesh, Devarajan, Nalini, Pandya, Medha, Mitra, Kartik, Ravi, Lokesh, Periyaswami, Vijayalakshmi

2022

Overview

Background The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. Results Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( − 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( − 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( − 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. Conclusion The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: ACE2 / Affinity / Algorithms / Amino acids / Analysis / Angiogenesis inhibitors / Angiotensin-converting enzyme 2 / Anti-virus software / Antiviral agents / Antiviral Agents - pharmacology / Antiviral drugs / Binding sites / Bioinformatics / Bioinformatics tools / Biomedical and Life Sciences / Computational Biology/Bioinformatics / Computer Appl. in Life Sciences / Coronaviruses / COVID-19 / COVID-19 - drug therapy / COVID-19 vaccines / Crystal structure / Dosage and administration / Free energy / Genistein / Genistein - pharmacology / Genomes / Glycoproteins / Humans / Hydrogen / Hydrogen bonding / Hydrogen bonds / Hydrophobicity / Innate immunity / Isoflavones / Life Sciences / Ligands / Microarrays / Molecular docking / Molecular Docking Simulation / Molecular dynamics / Mutation / Phyto compounds / Priming / Proteins / Proteolysis / Quercetin / Quercetin - pharmacology / SARS-CoV-2 / SARS-Cov-2 coronavirus / Serine / Serine Endopeptidases / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus / Spike protein / Substrates / Therapeutic targets / Transmembrane serine protease 2 / Viral diseases / Viral infections / Virus Internalization