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Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings.

Authors :
Dong, Jie
Varbanov, Mihayl
Philippot, Stéphanie
Vreken, Fanny
Zeng, Wen-bin
Blay, Vincent
Source :
Journal of Enzyme Inhibition & Medicinal Chemistry. Dec2023, Vol. 38 Issue 1, p24-35. 12p.
Publication Year :
2023

Abstract

Ligand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, Mpro. The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico. Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant Mpro, with half-maximal inhibitory concentration values (IC50) in the range 0.18–18.82 μM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus Mpro was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14756366
Volume :
38
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Enzyme Inhibition & Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
174161056
Full Text :
https://doi.org/10.1080/14756366.2022.2132486