Molecular Docking and Simulation Approach for Mutational Analysis in International Isolates and Drug Repurposing Against SARS-CoV-2 Spike Protein

The present study identified the binding interaction of potential drug candidates and validated the drug candidates using computational methods which lead a way for in vitro and in vivo studies. As the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is the pathogen responsible for coronavirus disease-19, it is spreading (COVID-19). Since its discovery, it has infected more than 0.65 billion people worldwide, and 6.67 million fatalities are expected by the middle of December 2022. SARS–CoV-2 enters the host cell by binding to viral surface glycoprotein (S protein) with human ACE2 (angiotensin-converting enzyme2). Since the molecular interaction of the spike protein (which contains the S1 and S2 sub-domains) with the host cells is regarded as a crucial step in the entry of the virus and the development of the disease, spike protein is a promising therapeutic target for antiviral medications. Currently, there are no efficient antiviral drugs to prevent COVID-19 infection. In this study, we have analyzed global 8,719 spike protein sequences from patients infected with SAR-CoV-2. These SAR-CoV-2 genome sequences were downloaded from the GISAID database. We have identified the spike protein sequence using an open reading frame (ORF) tool. All spike protein amino acid sequences are subjected to multiple sequence alignment (MSA) with the Wuhan strain spike protein sequence serving as the query sequence. It shows all SAR-CoV strain spike proteins are 99.8% identical. In the mutational analysis, we found 639 mutations in the spike protein sequence of SARS-CoV-2 and identified/highlighted 20 common mutations L5F, T22I, T29I, H49Y, L54F, V90F, S98F, S221L, S254F, V367F, A520S, T572I, D614G, H655Y, P809S, A879S, D936Y, A1020S, A1078S, and H1101Y. Further, we have analyzed the crystal structure of the 2019-nCoV chimeric receptor-binding complex with ACE2 (PDB ID: 6VW1) as a major target protein. The spike receptor binding protein (RBD) was used as the target region for our studies with FDA-approved drugs for repurposing, and identified a few anti-SARS-CoV2 potential drugs (Silmitasertib, AC-55541, Merimepodib, XL413, AZ3451) based on their docking score and binding mode calculations expected to strongly bind to motifs of ACE2 receptor and may show impart relief in COVID-19 patients. All these compounds have exhibited excellent binding capacity to SARS-CoV-2 RBD protein. These compounds may be effective to control or stop the viral entry and further infection, as well our study paves a way for further in vivo studies as well clinical trials.