Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

27 May 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations.



Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.

Keywords

COVID-19 virus (SARS-CoV-2)
Main Protease Mpro
3CLpro
Molecular Dynamics Simulation Study
Drug Binding
microsecond dynamics simulations

Supplementary materials

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CoV2-7inhibitors-supplement-newest-v282-submitted
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CoV2-7inhibitors-sample-movie-indinavir-6microseconds
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Supplementary weblinks

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