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

Abstract

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.

Impact of TMPRSS2 Expression, Mutation Prognostics, and Small Molecule (CD, AD, TQ, and TQFL12) Inhibition on Pan-Cancer Tumors and Susceptibility to SARS-CoV-2

“…Molecular docking analysis has predicted that small molecules have functional inhibitory effects on TMPRSS2 [ 21 ]. Thus, we investigated whether small molecules (CD, AD, TQ, and TQFL12) regulate TMPRSS2 expression.…”

“…Targeting SARS-CoV-2 entry factors, including TMPRSS2, may be a therapeutic strategy against COVID-19 [ 32 , 33 , 34 ]. Molecular docking analysis has predicted that small molecules have a functional inhibitory effect on TMPRSS2 [ 21 ]. Many dietary flavonoids show promising multitarget activities against SARS-CoV-2 [ 35 ].…”

Molecular Docking and Dynamic Simulation to Identify α7nAChR Binding Affinity of Flavonoids for the Treatment of Alzheimer's Disease

“…By using UCSF Chimera (version 1.14) unwanted heteroatoms, water molecules, metal ions, ligands, and extra chains were removed, polar hydrogens were added, non‐polar hydrogens were merged and Gasteiger charges for each of the atoms were computed [31] . The structures of fifty flavonoids enlisted in Table 1 were drawn using ChemSketch (http://www.acdlabs.com) [32] and prepared by adding polar hydrogens and optimized by applying Gasteiger charges [33] . All optimized ligands were saved in “.pdbqt format” for molecular docking analysis using Auto Dock Vina [31]…”

“…[31] The structures of fifty flavonoids enlisted in Table 1 were drawn using ChemSketch (www.acdlabs.com) [32] and prepared by adding polar hydrogens and optimized by applying Gasteiger charges. [33] All optimized ligands were saved in ".pdbqt format" for molecular docking analysis using Auto Dock Vina. [31]…”

Computational screening for investigating the synergistic regulatory potential of drugs and phytochemicals in combination with 2-deoxy-D-glucose against SARS-CoV-2

“…Redocking studies were executed to validate the compounds showing the best binding energy obtained by blind docking. We analyzed the active site residues of all three targets from available literature [ 23 , 24 ] and performed individual ligand docking and MLSD with the above protocol [ 25 , 26 ]. The best poses were selected based on maximum interactions depicted for minimum binding energy conformations, and these interactions between protein–ligand complexes were then visualized using the Discovery studio software.…”