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. 2022 Sep;40(15):7167-7182.
doi: 10.1080/07391102.2021.1910571. Epub 2021 Apr 13.

Inhibition of SARS-CoV-2 main protease: a repurposing study that targets the dimer interface of the protein

Hanife Pekel  1   2 , Metehan Ilter  3 , Ozge Sensoy  2   4
Affiliations

Inhibition of SARS-CoV-2 main protease: a repurposing study that targets the dimer interface of the protein

Hanife Pekel et al. J Biomol Struct Dyn. 2022 Sep.

Abstract

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. Herein, we aimed at having a holistic understanding of conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (Mpro) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of apo and α-ketoamide 13b-bound Mpro homodimer. Analysis of trajectories pertaining to apo Mpro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by α-ketoamide 13b on the catalytic dyad of Mpro. Furthermore, ZINC23881687 stably interacted with catalytically important residues Glu166 and Ser1 and the target site throughout the simulation. However, it gave positive binding energy, presumably, due to displaying higher flexibility that might dominate the entropic term, which is not included in the MM-PBSA method. Finally, ZINC20425029, whose mode of action was different, modulated dynamical properties of catalytically important residue, Ala285. As such, this study presents valuable findings that might be used in the development of novel therapeutics against Mpro.Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; drug repurposing; main protease; molecular dynamics; novel target site.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
The backbone root-mean-square fluctuations of subunit (a) A and (b) B for apo (PDB ID: 6Y2E) (blue) and holo (PDB ID: 6Y2F) (red) forms were calculated from the obtained trajectories.
Figure 2.
Figure 2.
The probability distributions of the distance measured between Cα atoms of Glu47 and Arg188 on subunit (a) A and (b) B. (c) Crystal structure of holo Mpro. α-ketoamide 13b is shown in licorice representation whereas the protein is shown in New Cartoon representation. The Cα atoms of Glu47 and Arg188 are shown in van der Waals representation.
Figure 3.
Figure 3.
The probability distributions of the distance which was measured between Nϵ2 atom of His41 and Sγ atom of Cys145 for subunit (a) A and (b) B.
Figure 4.
Figure 4.
The probability distribution of the distance which was measured between OE2 atom of Glu166 on subunit A and N atom of Ser1 on subunit B.
Figure 5.
Figure 5.
The probability distribution of the distance which was measured between Cα atom of Glu47 and Arg188 on subunit A.
Figure 6.
Figure 6.
(a) The identified binding pocket was shown on 3D structure of Mpro in surface representation, which adopted State 1. The protein was shown in New Cartoon representation. The binding poses of (b) ZINC02948810, (c) ZINC39362669, (d) diosmin, and (e) eluxadoline within the pocket were also shown (Stone, 1998).
Figure 7.
Figure 7.
(a) The identified binding cavity was shown on Mpro adopting State 2. The pocket was depicted in surface representation while the protein was shown in New Cartoon representation. The binding poses of (b) ZINC20425029, and (c) ZINC23881687 were depicted (Stone, 1998).
Figure 8.
Figure 8.
The probability distributions pertaining to distance which was measured between Cα atoms of Glu47 and Arg188 on subunit (a) A and (b) B. The probability distributions pertaining to distance which was measured between Nϵ2 atom of His41 and Sγ atom of Cys145 on subunit (c) A and (d) B.
Figure 9.
Figure 9.
The probability distributions pertaining to distance which was measured between Cα atoms of Glu47 and Arg188 on subunit (a) A and (b) B. The probability distribution pertaining to distance which was measured between Nϵ2 atom of His41 and Sγ atom of Cys145 on subunit (c) A and (d) B.
Figure 10.
Figure 10.
The probability distribution pertaining to distance which was measured between Cα atoms of Glu47 and Arg188 on subunit (a) A and (b) B. The probability distribution pertaining to distance which was measured between Nϵ2 atom of His41 and Sγ atom of Cys145 on subunit (c) A and (d) B.
Figure 11.
Figure 11.
The probability distributions of distances measured between Cα atoms of Ala285 on both subunits.
Figure 12.
Figure 12.
Hydrogen bond occupancies of the ligands with Glu166A and Ser1B.
Figure 13.
Figure 13.
2D projections of subunit A of (a) eluxadoline- and (c) ZINC23881687-bound systems as well as subunit B of the (b) eluxadoline- and (d) ZINC23881687-bound systems with respect to the first two eigenvectors of holo Mpro. The first and second principal components of subunit A count for 20.368% and 16.045%, whereas those of subunit B account for 20.715% and 12.158%, respectively.
Figure 14.
Figure 14.
The projections of (a) α-ketoamide 13b-, (b) eluxadoline-, and (c) ZINC23881687-bound Mpro complexes with respect to the first eigenvectors of the systems.
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