SARS-CoV-2 pandemic has claimed millions of lives across the world. As of June 2020, there is no FDA approved antiviral therapy to eradicate this dreadful virus. In this study, drug re-purposing and computational approaches were employed to identify high affinity inhibitors of SARS-CoV-2 Main protease (3CLpro), Papain-like protease (PLpro) and the receptor domain of Spike protein. Molecular docking on 40 derivatives of standard drugs (Remdesivir, Lopinavir and Theophylline) led to the identification of R10, R2 and L9 as potential inhibitors of 3CLpro, PLpro and Spike protein, respectively. The binding affinity of R10, R2 and L9 towards 3CLpro, PLpro and Spike protein were 4.03 × 10⁶, 3.72 × 10⁴ and 1.31 × 10⁴ M⁻¹, respectively. These inhibitors interact with the active site or catalytic amino acid residues of 3CLpro, PLpro and Spike protein. We also examined the stability and dynamic behavior of protein-inhibitor complex by employing molecular dynamics simulation. RMSDs, RMSFs and variation in secondary structure of target proteins alone or in complex with their respective inhibitors were used to ascertain the integrity of proteins’ structure during simulation. Moreover, physicochemical and ADMET properties of R10, R2 and L9 along with Remdesivir, Lopinavir and Theophylline were determined. In vitro and In vivo studies are needed to further validate the potential of these derivatives before they can be developed into potential drug molecules.

Communicated by Ramaswamy H. Sarma