Repurposing drugs and identification of inhibitors of integral proteins (spike protein and main protease) of SARS-CoV-2.

The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International concern. As part of the efforts to discover lead compounds for clinical use, 53 molecules were screened using molecular docking and dynamic simulations (MDS) techniques to identify potential inhibitors of SARS-CoV-2 spike protein (COVID-19 S) and main protease (COVID-19 M) or both. Lopinavir (LPV), nelfinavir (NEF), hydroxychloroquine (HCQ), remdesivir (RDV) and an irreversible inhibitor of SARS-CoV (N3) were used as standard drugs for COVID-19 M, while zafirlukast (ZFK) and cefoperazone (CSP)) as standard drugs for COVID-19 S. After 100ns of MDS, with reference to standard drugs (N3, -52.463 Kcal/mol, NEF, -51.618 Kcal/mol, RDV, -48.780 Kcal/mol, LPV, -46.788 Kcal/mol, DRV, -33.655 Kcal/mol and HCQ, -21.065 Kcal/mol), five molecules, HCR, GRN, C3G, EGCG, and K7G were predicted to be promising inhibitors of COVID-19 M with binding energies of -53.877kcal/mol, -50.653 Kcal/mol, -48.600kcal/mol, -47.798kcal/mol and -46.902kcal/mol, respectively. These lead molecules were then docked at receptor-binding domain (RBD) of COVID-19 S to examine their inhibitory effects. C3G, GRN and K7G exhibited higher binding energies of -42.310kcal/mol, -32.210kcal/mol, -26.922kcal/mol than the recorded values for the reference drugs (CSP, -35.509kcal/mol, ZFK, -24.242kcal/mol), respectively. The results of the binding energy and structural analyses from this study revealed that C3G, GRN and K7G could serve as potential dual inhibitors of COVID-19 S and COVID-19 M, while HCR and EGCG would be inhibitors of COVID-19 Mpro.Communicated by Ramaswamy H. Sarma.