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SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations by Roman S. Tumskiy; Anastasiia V. Tumskaia; Iraida N. Klochkova; Rudy J. Richardson is a Medicine article available to read on EtoBox.

What is SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations about?

The main (Mpro) and papain-like (PLpro) proteases are highly conserved viral proteins essential for replication of the COVID-19 virus, SARS-COV-2. Therefore, a logical plan for producing new drugs against this pathogen is to discover inhibitors of these enzymes. Accordingly, the goal of the present work was to devise a computational approach to design, characterize, and select compounds predicted to be potent dual inhibitors – effective against both Mpro and PLpro. The first step employed LigDream, an artificial neural network, to create a virtual ligand library. Ligands with computed ADMET profiles indicating drug-like properties and low mammalian toxicity were selected for further study. Initial docking of these ligands into the active sites of Mpro and PLpro was done with GOLD, and the highest-scoring ligands were redocked with AutoDock Vina to determine binding free energies (ΔG). Compounds 89–00, 89–07, 89–32, and 89–38 exhibited favorable ΔG values for Mpro (−7.6 to −8.7 kcal/mol) and PLpro (−9.1 to −9.7 kcal/mol). Global docking of selected compounds with the Mpro dimer identified prospective allosteric inhibitors 89–00, 89–27, and 89–40 (ΔG -8.2 to −8.9 kcal/mol). Molecular

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Author

Roman S. Tumskiy; Anastasiia V. Tumskaia; Iraida N. Klochkova; Rudy J. Richardson

Publisher

Elsevier BV

Published

2023

Language

EN

Field

Medicine (Physical Sciences)