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. 2021 Jun 26;10(7):589.
doi: 10.3390/biology10070589.

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

Shafi Mahmud  1 , Suvro Biswas  2 , Gobindo Kumar Paul  1 , Mohasana Akter Mita  2 , Maria Meha Promi  2 , Shamima Afrose  2 , Md Robiul Hasan  2 , Shahriar Zaman  1 , Md Salah Uddin  1 , Kuldeep Dhama  3 , Talha Bin Emran  4 , Md Abu Saleh  1 , Jesus Simal-Gandara  5
Affiliations

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

Shafi Mahmud et al. Biology (Basel). .

Abstract

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of -8.4, -8.5, and -8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein-compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

Keywords: ADMET; SARS-CoV-2; dynamics simulation; molecular docking; phytochemicals.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Two-dimensional (2D) chemical structures of (a) epicatechin-3-O-gallate, (b) psi-taraxasterol, and (c) catechin gallate. The structures were drawn using MarvinSketch software.
Figure 2
Figure 2
The various binding modes for the selected compounds within the active and catalytic sites of the SARS-CoV-2 main protease. (A) epicatechin-3-O-gallate, (B) psi-taraxasterol, and (C) catechin gallate.
Figure 3
Figure 3
Time series analyses for all three simulated systems. (a) RMSD analysis for the alpha carbon atoms, (b) protein volume with expansion analysis, (c) degree of rigidity and compactness analysis, (d) hydrogen bond analysis, and (e) flexibility analysis of amino acid residues.
Figure 4
Figure 4
Superimpositions of the drug–protein complex before and after molecular dynamics. Purple color indicates the baseline structure and dark blue indicates the structure after molecular dynamics. (a) Epicatechin-3-O-gallate, (b) Psi-taraxasterol, and (c) Catechin gallate.
Figure 5
Figure 5
Surface views for the docked complex in the molecular dynamics simulation. The snapshots were taken at 25, 50, 75, and 100 ns, respectively, for (+)-epicatechin-3-O-gallate and the Mpro complex.
Figure 6
Figure 6
The surface view and the binding pockets between psi-taraxasterol and Mpro complex, with snapshots at 25, 50, 75, and 100 ns.
Figure 7
Figure 7
The surface view of the docked (-)-catechin gallate and Mpro complex, with snapshots at 25, 50, 75, and 100 ns.
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