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. 2021 Sep;14(9):103315.
doi: 10.1016/j.arabjc.2021.103315. Epub 2021 Jul 14.

Antiviral peptides against the main protease of SARS-CoV-2: A molecular docking and dynamics study

Shafi Mahmud  1 , Suvro Biswas  2 , Gobindo Kumar Paul  1 , Mohasana Akter Mita  2 , Shamima Afrose  2 , Md Robiul Hasan  2 , Mst Sharmin Sultana Shimu  2 , Mohammad Abu Raihan Uddin  3 , Md Salah Uddin  1 , Shahriar Zaman  1 , K M Kaderi Kibria  4 , Md Arif Khan  5 , Talha Bin Emran  6 , Md Abu Saleh  1
Affiliations

Antiviral peptides against the main protease of SARS-CoV-2: A molecular docking and dynamics study

Shafi Mahmud et al. Arab J Chem. 2021 Sep.

Abstract

The recent coronavirus outbreak has changed the world's economy and health sectors due to the high mortality and transmission rates. Because the development of new effective vaccines or treatments against the virus can take time, an urgent need exists for the rapid development and design of new drug candidates to combat this pathogen. Here, we obtained antiviral peptides obtained from the data repository of antimicrobial peptides (DRAMP) and screened their predicted tertiary structures for the ability to inhibit the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using multiple combinatorial docking programs, including PatchDock, FireDock, and ClusPro. The four best peptides, DRAMP00877, DRAMP02333, DRAMP02669, and DRAMP03804, had binding energies of -1125.3, -1084.5, -1005.2, and -924.2 Kcal/mol, respectively, as determined using ClusPro, and binding energies of -55.37, -50.96, -49.25, -54.81 Kcal/mol, respectively, as determined using FireDock, which were better binding energy values than observed for other peptide molecules. These peptides were found to bind with the active cavity of the SARS-CoV-2 main protease; at Glu166, Cys145, Asn142, Phe140, and Met165, in addition to the substrate-binding sites, Domain 2 and Domain 3, whereas fewer interactions were observed with Domain 1. The docking studies were further confirmed by a molecular dynamics simulation study, in which several descriptors, including the root-mean-square difference (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), and hydrogen bond formation, confirmed the stable nature of the peptide-main protease complexes. Toxicity and allergenicity studies confirmed the non-allergenic nature of the peptides. This present study suggests that these identified antiviral peptide molecules might inhibit the main protease of SARS-CoV-2, although further wet-lab experiments remain necessary to verify these findings.

Keywords: Lead identification; Molecular dynamics; Peptide; Peptide–protein docking; SARS-CoV-2.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The best four peptide molecules based on binding affinity in docking program; (a) DRAMP00877, (b) DRAMP02333, (c) DRAMP02669, (d) DRAMP03804 peptide molecules.
Fig. 2
Fig. 2
The non-bonded interaction of the DRAMP00877, DRAMP02333, DRAMP02669, DRAMP03804 peptides and main protease from SARS-CoV-2 at certain simulation times. Here, (A), (B), (C), (D), represents the binding interactions of the DRAMP00877, DRAMP02333, DRAMP02669, DRAMP03804 peptides and main protease complexes after 0 ns time respectively.
Fig. 3
Fig. 3
The molecular dynamics simulation of the peptide and main protease complex, here (a) root mean square deviation of the c-alpha atoms, (b) solvent accessible surface area, (c) radius of gyration, (d) hydrogen bonding of the complexes, (e) root mean square fluctuation of the complexes to understand the flexibility of the amino acid residue.
Fig. 4
Fig. 4
The superimposition of the Pre and Post MD structure; (A) Pre and Post MD structure of DRAMP00877 peptide, (B) Pre and Post structure of DRAMP02333 peptide, (C) superimposed structure of DRAMP02669 peptide, (D) superimposed structure of DRAMP03804 peptide. The figure was analyzed in Discovery Studio software package.
Fig. 5
Fig. 5
The binding free energy of the top 4 peptide and protein complexes which were calculated by MM-PBSA methods.
See this image and copyright information in PMC

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