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Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Hajbabaie, Roxanna 
Harper, Matthew T 

Abstract

The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein-ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.

Description

Keywords

COVID-19, SARS-CoV-2 Mpro, coronavirus, drug discovery, fragment-guided, in silico, main protease, molecular docking, natural products, pharmacophore, COVID-19, Coronavirus 3C Proteases, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Pandemics, SARS-CoV-2, COVID-19 Drug Treatment

Journal Title

Molecules

Conference Name

Journal ISSN

1420-3049
1420-3049

Volume Title

25

Publisher

MDPI AG

Rights

All rights reserved
Sponsorship
British Heart Foundation (PG/17/45/33071)