Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach.

The pandemic caused by novel coronavirus disease 2019 (COVID-19) infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M. However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with residues, that are mainly conserved and can be targeted for structure- and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for studies.Communicated by Ramaswamy H. Sarma.