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

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J Biomol Struct Dyn. 2020 May 12:1-26. doi: 10.1080/07391102.2020.1768151. [Epub ahead of print]
Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach.


Mittal L¹, Kumari A¹, Srivastava M¹, Singh M¹, Asthana S¹.

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Abstract

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 in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M^pro) 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^pro 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^pro. 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 hot-spot 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 in-vitro studies.



KEYWORDS:

COVID-19; Mpro protease; SARS-CoV-2; Virtual screening; binding free energy; molecular docking analysis


PMID:32396769DOI:10.1080/07391102.2020.1768151