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

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

doi:10.1016/j.compbiomed.2022.106449

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

Comput Biol Med. 2023 Feb:153:106449. doi: 10.1016/j.compbiomed.2022.106449. Epub 2022 Dec 23.

Authors

Roman S Tumskiy¹, Anastasiia V Tumskaia², Iraida N Klochkova², Rudy J Richardson³

Affiliations

¹ Institute of Biochemistry and Physiology of Plants and Microorganisms - Subdivision of the Federal State Budgetary Research Institution Saratov Federal Scientific Centre of the Russian Academy of Sciences (IBPPM RAS), 13 Prospekt Entuziastov, Saratov, 410049, Russia.
² Chemistry Institute, Saratov State University, 83 Astrakhanskaya Str, Saratov, 410012, Russia.
³ Toxicology Program, Molecular Simulations Laboratory, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Institute for Data Science, Ann Arbor, MI, 48109, USA; Michigan Institute for Computational Discovery and Engineering, Ann Arbor, MI, 48109, USA. Electronic address: rjrich@umich.edu.

Abstract

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 dynamics simulations performed on Mpro and PLpro active site complexes with the four top-scoring ligands from Vina demonstrated that the most stable complexes were formed with compounds 89-32 and 89-38. Overall, the present computational strategy generated new compounds with predicted drug-like characteristics, low mammalian toxicity, and high inhibitory potencies against both target proteases to form stable complexes. Further preclinical studies will be required to validate the in silico findings before the lead compounds could be considered for clinical trials.

Keywords: ADMET; COVID-19; Heterocyclic compounds; In silico drug design; Molecular docking; Molecular dynamics simulation; Mpro/PLpro inhibitors; Nirmatrelvir; Pyrazolopyridazines; Tetrazoles.

MeSH terms

Animals
COVID-19*
Ligands
Mammals
Molecular Docking Simulation
Molecular Dynamics Simulation
Neural Networks, Computer
Peptide Hydrolases*
Prospective Studies
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

Peptide Hydrolases
Ligands
Protease Inhibitors