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. 2022 Jul:146:105572.
doi: 10.1016/j.compbiomed.2022.105572. Epub 2022 Apr 29.

Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

Rahul Singh  1 , Vijay Kumar Bhardwaj  1 , Pralay Das  2 , Dhananjay Bhattacherjee  3 , Grigory V Zyryanov  4 , Rituraj Purohit  5
Affiliations

Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

Rahul Singh et al. Comput Biol Med. 2022 Jul.

Abstract

Background: The SARS-CoV-2 main protease (Mpro) is an attractive target in the COVID-19 drug development process. It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the absence of identical cleavage specificity in human cell proteases, targeting Mpro with chemical compounds can obstruct the replication of the virus.

Methods: To explore the potential binding mechanisms of 1,2,3-triazole scaffolds in comparison to co-crystallized inhibitors 11a and 11b towards Mpro, we herein utilized molecular dynamics and enhanced sampling simulation studies.

Results and conclusion: All the 1,2,3-triazole scaffolds interacted with catalytic residues (Cys145 and His41) and binding pocket residues of Mpro involving Met165, Glu166, Ser144, Gln189, His163, and Met49. Furthermore, the adequate binding free energy and potential mean force of the topmost compound 3h was comparable to the experimental inhibitors 11a and 11b of Mpro. Overall, the current analysis could be beneficial in developing the SARS-CoV-2 Mpro potential inhibitors.

Keywords: 1,2,3-Triazole; Free energy landscape; MD simulation; MM-PBSA; Umbrella sampling simulation.

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Conflict of interest statement

There are no competing interests declared by the authors.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
3-D binding poses showing SARS-CoV-2 Mpro complexes with co-crystallized and 1,2,3-triazole scaffolds.
Fig. 2
Fig. 2
The Root Mean Square Deviation (RMSD) graph of the Mpro C α-atoms in complex with 11a (black), 11b (blue), 3f (green), 3g (red), 3h (dark green), 3j (cyan), 5d (magenta), 5e (violet), and 3i (yellow).
Fig. 3
Fig. 3
Radius of gyration (Rg) plot depicting the changes observed in the conformational behavior of Mpro complexes 11a (black), 11b (blue), 3f (green), 3g (red), 3h (dark green), 3j (cyan), 5d (magenta), 5e (violet), and 3i (yellow).
Fig. 4
Fig. 4
Pictorial representation of conformational flexibility using ensemble cluster analysis of Mpro in complex with (a) 11a, (b) 11b, (c) 3f, (d) 3g, (e) 3h, (f) 3j, (g) 5d, (h) 5e, and (i) 3i.
Fig. 5
Fig. 5
Free energy landscape of Mpro as a function of first two principal components PC1 and PC2 (a) 11a, (b) 11b, and (c) 3h.
Fig. 6
Fig. 6
Potential of mean force (PMF) curves obtained after umbrella sampling for the co-crystallized and the best selected compound in complex with Mpro SARS-CoV-2.
See this image and copyright information in PMC

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