In Silico Structure-Based Repositioning of Approved Drugs for Spike Glycoprotein S2 Domain Fusion Peptide of SARS-CoV-2: Rationale from Molecular Dynamics and Binding Free Energy Calculations

Abstract

The membrane-anchored spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a pivotal role in directing the fusion of the virus particle mediated by the host cell receptor angiotensin-converting enzyme 2 (ACE-2). The fusion peptide region of the S protein S2 domain provides SARS-CoV-2 with the biological machinery needed for direct fusion to the host lipid membrane. In our present study, computer-aided drug design strategies were used for the identification of FDA-approved small molecules using the optimal structure of the S2 domain, which exhibits optimal interaction ratios, structural features, and energy variables, which were evaluated based on their performances in molecular docking, molecular dynamics simulations, molecular mechanics/generalized Born model and solvent accessibility binding free energy calculations of molecular dynamics trajectories, and statistical inferences. Among the 2,625 FDA-approved small molecules, chloramphenicol succinate, imipenem, and imidurea turned out to be the molecules that bound the best at the fusion peptide hydrophobic pocket. The principal interactions of the selected molecules suggest that the potential binding site at the fusion peptide region is centralized amid the Lys790, Thr791, Lys795, Asp808, and Gln872 residues. IMPORTANCE The present study provides the structural identification of the viable binding residues of the SARS-CoV-2 S2 fusion peptide region, which holds prime importance in the virus’s host cell fusion and entry mechanism. The classical molecular mechanics simulations were set on values that mimic physiological standards for a good approximation of the dynamic behavior of selected drugs in biological systems. The drug molecules screened and analyzed here have relevant antiviral properties, which are reported here and which might hint toward their utilization in the coronavirus disease 2019 (COVID-19) pandemic owing to their attributes of binding to the fusion protein binding region shown in this study.

Structural and conformational analysis of SARS CoV 2 N-CTD revealing monomeric and dimeric active sites during the RNA-binding and stabilization: Insights towards potential inhibitors for N-CTD

“…Further, N-protein's structural study reveals that the residues of CTD are involved in RNA-binding and amino acid residues between 248-270 positions are essential for nucleotide-binding [ 20 ]. Computational aided drug designing has led to the identification of various targets and rapidly screening their possible inhibitors without much economic and resources burden in the shortest time possible [ 26 , 27 ]. Various in vitro clinically relevant models are also developed that can help in testing potential drug candidates against the novel targets to support the findings of the in silico studies [ 27 ].…”

Molecular biology of the SARs‐CoV‐2 spike protein: A review of current knowledge

“…The potential lipids‐binding residues in FP of SARS‐CoV‐2 is centralized amid in Lys790, Thr791, Lys795, Asp808, and Gln872 residues, contributing to lipid interaction and penetration. 48 Surface models predicted that the FP of SARS‐CoV‐2 S was organized in a more compact conformation than that of SARS‐CoV S. 49 Cleavage at S2′ exposes the FP domain, which, in turn, inserted in the host membrane triggering the viral fusion. 22 With strong membrane‐perturbing capacities, 50 FP plays a crucial role in cell fusion.…”

Milk Peptides as Novel Multi‐Targeted Therapeutic Candidates for SARS-CoV2

“…An in silico study to repurpose FDA-approved drugs as SARS-CoV2 spike protein inhibitors via virtual screening revealed that the potent compounds bind at the RBD-ACE2 interface involving diverse amino acids (319–530) of SARS-CoV2 spike protein. A detailed analysis of interface residues revealed that a stretch of the SARS-CoV2 spike protein (339–506) to be interacting majorly with the ACE2 (340–468) and hence, the same site was chosen for docking based screening of milk peptides [ 21 ].…”