Fisetin 8-C-glucoside as entry inhibitor in SARS CoV-2 infection: molecular modelling study

Abstract

Coronaviruses are RNA viruses that infect varied species including humans. TMPRSS2 is gateway for SARS CoV-2 entry into the host cell. It causes proteolytic activation of spike protein and discharge of the peptide into host cell. The TMPRSS2 inhibition could be one of the approaches to stop the viral entry, therefore, interaction pattern and binding energies for Fisetin and TMPRSS2 have been explored in the present study. TMPRSS2 peptide was used for homology modelling and then for further study. Molecular docking score and MMGBSA Binding energy of Fisetin was better than Nafamostat, a known inhibitor of TMPRSS2. Post docking MM-GBSA free energy for Fisetin and Nafamostat was À42.78 and À21.11 kcal/mol, respectively. Fisetin forms H bond with Val 25, His 41, Lys 42, Lys 45, Glu 44, Ser186. Nafamostat formed H bonds with Lys 85, Asp 90, Asp 203. RMSD plots of TMPRSS2, TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex showed stable profile with very small fluctuation during entire simulation of 150 ns. Significant decrease in TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex fluctuation occurred around His 41, Glu 44, Gly 136, Ser 186 in RMSF study. During simulation Fisetin interaction was observed with residues Val 25, His 41, Glu 44, Lys 45, Lys 87, Gly 136, Gln 183, Ser 186 likewise interaction of Nafamostat with Lys 85, Asp 90, Asn 163, Asp 203 and Ser 205. Post simulation MM-GBSA free energy was found to be À51.87 ± 4.3 and À48.23 ± 4.39 kcal/mol for TMPRSS2 with Fisetin and Nafamostat, respectively.

Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations

“…The root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) of the structure of the protein–ligand complex were investigated using the OPLS3 (Optimized Kanhesia for Liquid Simulations) force fields with regard to a 150 ns simulation. 37 , 38 For the binding energy investigation, Prime-MM/GBSA (molecular mechanics/generalized Born surface area) was employed. 39 This model uses a Gaussian surface rather than a van der Waals surface to represent the solvent accessible surface area.…”

“…For the protein–ligand complex, 150 ns MD simulations were run, and trajectories were generated every 150 ps with an energy recording interval of 1.2 ps. The root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) of the structure of the protein–ligand complex were investigated using the OPLS3 (Optimized Kanhesia for Liquid Simulations) force fields with regard to a 150 ns simulation. , For the binding energy investigation, Prime-MM/GBSA (molecular mechanics/generalized Born surface area) was employed . This model uses a Gaussian surface rather than a van der Waals surface to represent the solvent accessible surface area. , The equations used for binding energy (Δ G bind ) calculations are the following: where E complex , E protein , and E ligand are the minimized energies for the protein–ligand complex, protein, and ligand, respectively; where G solv‑complex , G solv‑protein and G solv‑ligand are the solvation energies for the protein–ligand complex, protein, and ligand, respectively; and where G SA‑complex , G SA‑protein , and G SA‑ligand are the surface area energies for the protein–ligand complex, protein, and ligand, respectively.…”

Identification of nut protein-derived peptides against SARS-CoV-2 spike protein and main protease

“…After the coronavirus enters the host cell, the viral messenger RNA is first translated into polyproteins, which are cleaved by two viral proteinases, papain-like protease (PLP) and main protease (M pro ) [ 9 , 10 ], to produce non-structural proteins essential for viral replication [ 11 ]. Blocking spike protein binding to ACE2 is an effective therapy for SARS-CoV-2 infection [ 12 ]. Therefore, the spike protein has emerged as a potential target for antiviral therapy, and the M pro is one of the most promising drug targets in coronaviruses [ 13 ].…”