Issue 48, 2022

Optimization of potential non-covalent inhibitors for the SARS-CoV-2 main protease inspected by a descriptor of the subpocket occupancy

Abstract

The main protease is regarded as an essential drug target for treating Coronavirus Disease 2019. In the present study, 13 marketed drugs were investigated to explore the possible binding mechanism, utilizing molecular docking, molecular dynamics simulation, and MM-PB(GB)SA binding energy calculations. Our results suggest that fusidic acid, polydatin, SEN-1269, AZD6482, and UNC-2327 have high binding affinities of more than 23 kcal mol−1. A descriptor was defined for the energetic occupancy of the subpocket, and it was found that S4 had a low occupancy of less than 10% on average. The molecular optimization of ADZ6482 via reinforcement learning algorithms was carried out to screen out three lead compounds, in which slight structural changes give more considerable binding energies and an occupancy of the S4 subpocket of up to 43%. The energetic occupancy could be a useful descriptor for evaluating the local binding affinity for drug design.

Graphical abstract: Optimization of potential non-covalent inhibitors for the SARS-CoV-2 main protease inspected by a descriptor of the subpocket occupancy

Supplementary files

Article information

Article type
Paper
Submitted
10 Aug 2022
Accepted
20 Nov 2022
First published
21 Nov 2022

Phys. Chem. Chem. Phys., 2022,24, 29940-29951

Optimization of potential non-covalent inhibitors for the SARS-CoV-2 main protease inspected by a descriptor of the subpocket occupancy

Y. Sun, B. Zhao, Y. Wang, Z. Chen, H. Zhang, L. Qu, Y. Zhao and J. Song, Phys. Chem. Chem. Phys., 2022, 24, 29940 DOI: 10.1039/D2CP03681A

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