Computational Prediction of the Molecular Mechanism of Statin Group of Drugs Against SARS-CoV-2 Pathogenesis

Abstract

\n BackgroundThe COVID-19 pandemic had raised a severe health concern across the globe, as most countries are fighting with the second wave of SARS-CoV-2 infection. Although several vaccines had cleared the clinical trials and are being administered in different countries, the degree of protection varies due to the emergence of novel viral strains. Moreover, no antiviral drug against SARS-CoV-2 was reported to date. Recently published reports on statin therapy on COVID-19 patients indicated that statin therapy is associated with a better clinical outcome and a significant reduction in mortality risk.MethodsBlind docking of the critical structural and functional proteins of SARS-CoV-2 like RNA-dependent RNA polymerase, M-protease of 3-CL-Pro, Helicase, and the Spike proteins ( wild type and mutants) with the statin molecules were performed using the Schrodinger docking tool. Prevalent mutations in the spike protein were determined by analyzing the SARS-CoV-2 genome sequences deposited in GISAID, using the NextAlign aligner tool. Wild type and mutant spike proteins were modeled using the Swiss Model server and subjected to energy minimization via YASARA server. The percentage of the allowed region was determined by the Ramachandran plot. The MD simulation studies of free protein templates and protein-ligand complex were performed using NAMD (Nanoscale Molecular Dynamics) program; v 2.8.ResultsWe observed that fluvastatin and pitavastatin showed fair binding affinities to RNA polymerase, 3-CL-Pro, and spike-double mutant with similar docking scores. But of all the target proteins, fluvastatin showed the strongest binding affinity to the helicase with the glide score, emodel score, and glide energy values of -11.333, -66.511 and -58.72 (kcal/mol), respectively. Pitavastatin having similar chemical properties like fluvastatin (logP and pKa values) exhibited strong biding affinities to RdRp, 3-CL-Pro, and S-double mutant. Additionally, molecular dynamics simulation confirmed the formation of a stable drug-protein complex. ConclusionThus our study shows that of all the statins, fluvastatin can bind to multiple target proteins of SARS-CoV-2, including the spike-mutant proteins. This property might contribute to the potent antiviral efficacy of this drug.