DELAVIRDINE AND DOLUTEGRAVIR AS POTENTIAL INHIBITORS OF SARS-COV-2 MAIN PROTEASE (Mpro): AN IN-SILICO STUDY

Abstract

The serine-type 3-chymotrypsin-like protease (3CL^pro) of CoVID-19 is an enzyme which carries out the proteolytic activity of two overlapping polyproteins; pp1a and pp1ab, and digests them into polypeptide. This functionality of such an enzyme is crucial for the replication cycle of the virus, thus making it an interesting target for searching and developing antivirals against CoVID-19 infections. Thereof, this study investigates the activity of 74 commercially available antivirals, besides the well-known antimalarials; chloroquine and hydroxychloroquine, towards 3CL^pro. Initially, the involved compounds were assessed according to their lowest energies of binding at the 3CL^pro’s catalytic binding site via virtual screening approach. Further assessment of the binding affinities of ten antivirals which owned the lowest binding energies, in addition to chloroquine and hydroxychloroquine, was achieved using molecular docking simulations to study compounds’ binding conformations and interactions at the active site of the target. Once assessed, only four antivirals; delavirdine, dolutegravir, raltegravir and vicriviroc, which interact with the catalytic dyad residues (CYS145 and HIS41) were studied using molecular dynamics and mechanics throughout 100 ns simulations. Results indicate that delavirdine and dolutegravir have a very comparable profile of hydrogen-bond interactions to that of the control molecule; N3-peptide-like irreversible inhibitor. Besides, both antivirals were able to maintain a sustainable degree of rigidity and protein folding throughout the simulations which relates to the amide bonds existing in their chemical structures that can act as a scissile bond. Still, these finding require further biological assessments which would drastically improve patients’ symptoms and reduce the need of hospitalisation.