Dual inhibitors of SARS-CoV-2 proteases: pharmacophore and molecular dynamics based drug repositioning and phytochemical leads.

Journal of Biomolecular Structure & Dynamics
Kartik MitraMukesh Doble

Abstract

SARS-related coronaviruses poses continual threat to humanity by rapidly mutating and emerging as severe pandemic outbreaks, including the current nCoV-19 pandemic. Hence a rapid drug repositioning and lead identification strategy are required to mitigate these outbreaks. We report a pharmacophore and molecular dynamics-based approach for drug repositioning and lead identification against dual targets (3CLp and PLp) of SARS-CoV-2. The pharmacophore model of 3CLp inhibitors was apolar with two aromatic and two H-bond acceptors, whereas that of PLp was relatively polar, bearing one aromatic and three H-bond acceptors. Pharmacophore-based virtual screening yielded six existing FDA-approved drugs and twelve natural products with both the pharmacophoric features. Among them are nelfinavir, tipranavir and licochalcone-D, which has shown better binding characteristics with both the proteases compared to lopinavir. The molecular dynamics revealed that the connecting loop (residues 176-199) of 3CLp is highly flexible, and hence, inhibitors should avoid high-affinity interactions with it. Lopinavir, due to its high affinity with the loop region, exhibited unstable binding. Further, the van der Waals size of the 3CLp inhibitors positively...Continue Reading

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Citations

Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Konstantina VougogiannopoulouAlexios-Leandros Skaltsounis
Jan 26, 2021·Journal, Genetic Engineering & Biotechnology·Haruna Isiyaku UmarProsper Obed Chukwuemeka
Apr 7, 2021·European Journal of Pharmacology·Dhananjay JadeMoola Joghee Nanjan
Aug 31, 2021·Computational and Structural Biotechnology Journal·Fangfang Yan, Feng Gao

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