In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global

public health emergency of unprecedented level. Therefore the need of a drug or vaccine that

counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome

of SARS-CoV-2 is translated into large polyprotein which further processed into different

nonstructural proteins to form viral replication complex by virtue of virus specific proteases:

main protease (3-CL protease) and papain protease. This indispensable function of main protease

in virus replication makes this enzyme a promising target for the development of inhibitors and

potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide

ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.

has revealed the potential inhibitor binding mechanism and the determinants responsible for

involved molecular interactions. Here, we have carried out a virtual screening and molecular

docking study of FDA approved drugs primarily targeted for other viral infections, to investigate

their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral

drugs, top ten of which on the basis of their bending energy score are further examined through

molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir

and Raltegravir among others binds in the active site of the protease with similar or higher

affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug

molecules tested in this study, further needs to be corroborated by carrying out biochemical and

structural investigation. Moreover, this study advances the potential use of existing drugs to be

investigated and used to contain the rapidly expanding SARS-CoV-2 infection.

Abstract