In silico prediction of mozenavir as a potential drug for SARS-CoV-2 infection via binding multiple drug targets

Abstract

Since the epidemic began in November 2019, no viable medicine against SARS-CoV-2 has been discovered. The typical medication discovery strategy requires several years of rigorous research and development as well as a significant financial commitment, which is not feasible in the face of the current epidemic. Through molecular docking and dynamic simulation studies, we used the FDA-approved drug mezonavir against the most important viral targets, including spike (S) glycoprotein, Transmembrane serine protease 2 (TMPRSS2), RNA-dependent RNA polymerase (RdRp), Main protease (Mpro), human angiotensin-converting enzyme 2 (ACE-2), and furin. These targets are critical for viral replication and infection propagation because they play a key role in replication/transcription and host cell recognition. Molecular docking revealed that the antiviral medication mozenavir showed a stronger affinity for SARS-CoV-2 target proteins than reference medicines in this investigation. We discovered that mozenavir increases the complex's stability and validates the molecular docking findings using molecular dynamics modeling. Furin, a target protein of COVID-19, has a greater binding affinity (-12.04 kcal/mol) than other COVID-19 target proteins, forming different hydrogen bonds and polar and hydrophobic interactions, suggesting that it might be used as an antiviral treatment against SARS-CoV-2. Overall, the present in silico results will be valuable in identifying crucial targets for subsequent experimental investigations that might help combat COVID-19 by blocking the protease furin's proteolytic activity.

Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19

“…7 ). These results were consistent with the RMSD plots for furin-mozenavir, furin-folic acid, and furin-folinic acid complexes [ 94 , 96 ]. However, same observation cannot be said about the unbound protein as the RMSD continued to rise even after 80 ns to levels around 0.3 nm.…”

“…The 29 compounds had binding energies ranging from − 9.0 to − 2.0 kcal.mol −1 [ 93 ]. Another study docked mozenavir with the furin protease using AutoDock and reported a binding energy of − 12.05 kcal.mol −1 as against the reference furin inhibitor decanoyl-RVKR-chloromethyl ketone which had a binding energy of − 6.89 kcal.mol −1 [ 94 ].…”

“…These interaction sites within the active site contain the catalytic triad Ser368, His194, and Asp153 which are important for ligand interactions. Aside these catalytic residues, other ligand binding residues include Trp254, Pro256, Val231, Asn295, Glu257, Gly255, Ala267, Asp233, Asp236, Tyr308, and Asp264 [ 93 , 94 ]. Mozenavir was previously shown in silico to interact with Tyr308, Gly265, Gly255, Asp154, and Val231 via hydrogen bonds and formed hydrophobic contacts with Glu236, Pro256, Trp254, Leu227, His194, Gly229, Asp264, Asp191, Glu230, and Gly229 [ 94 ].…”

“…Aside these catalytic residues, other ligand binding residues include Trp254, Pro256, Val231, Asn295, Glu257, Gly255, Ala267, Asp233, Asp236, Tyr308, and Asp264 [ 93 , 94 ]. Mozenavir was previously shown in silico to interact with Tyr308, Gly265, Gly255, Asp154, and Val231 via hydrogen bonds and formed hydrophobic contacts with Glu236, Pro256, Trp254, Leu227, His194, Gly229, Asp264, Asp191, Glu230, and Gly229 [ 94 ]. Imatinib forms two hydrogen bonds with Glu236 and Gly255, and interacts with the furin protease via weak hydrophobic contacts with Val231, Pro256, Trp254, and Gly294 [ 29 ].…”

Synthesis, crystal structure elucidation, DFT analysis, drug‐likeness and ADMET evaluation and molecular docking studies of triazole derivatives: Binary inhibition of spike protein and ACE2 receptor protein of COVID‐19

“…The contact surface of ACE2 that binds to RBD has been chosen as the best active site of ACE2 receptor protein. [ 39 ] The important amino acids of ACE2 surface that binds with RBD area are ASP350, HIS401, PHE40, GLU375, TRP349, ASN394, LYS353, THR371, GLY326, ARG393, ARG514, and PRO399. With the help of AutoGrid, a grid box was formed in active site ACE2 receptor protein of 7DF4 with grid center coordinates X = 171.680; Y = 214.638; Z = 285.757.…”