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. 2021 Oct 5:1:717141.
doi: 10.3389/fbinf.2021.717141. eCollection 2021.

Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

Shafi Mahmud  1 , Md Robiul Hasan  2 , Suvro Biswas  2 , Gobindo Kumar Paul  1 , Shamima Afrose  2 , Mohsana Akter Mita  2 , Mst Sharmin Sultana Shimu  2 , Maria Meha Promi  2 , Umme Hani  3 , Mohamed Rahamathulla  3 , Md Arif Khan  4 , Shahriar Zaman  1 , Md Salah Uddin  1 , Mohammed Rahmatullah  4 , Rownak Jahan  4 , Ali M Alqahtani  5 , Md Abu Saleh  1 , Talha Bin Emran  6
Affiliations

Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

Shafi Mahmud et al. Front Bioinform. .

Abstract

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of -8.3, -8.6, and -8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

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

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chemical structures (2D) of Medicagol (A), Faradiol (B), and Flavanthrin (C). The structures were drawn using Marvin Sketch software.
FIGURE 2
FIGURE 2
The figure illustrates non-bonded interactions of the docked complexes for top three compounds within the active and catalytic sites of the main protease. (A) Medicagol, (B) Faradiol, and (C) Flavanthrin.
FIGURE 3
FIGURE 3
Time series analysis of all simulated systems. Panels from (A) to (D) indicate the RMSD analysis of alpha carbon atoms (A), protein volume with expansion analysis (B), degree of rigidity and compactness analysis (C), and flexibility analysis of amino acid residues (D).
FIGURE 4
FIGURE 4
The binding free energy of the control and top three phytochemical compounds where more positive score indicates more better bindings.
FIGURE 5
FIGURE 5
The hydrogen bond analysis from the simulation trajectories where every snapshot were taken into consideration for the graph generations. The ( A ) hydrogen bond between solute and the solvents, and ( B ) the hydrogen bond in the solute.
FIGURE 6
FIGURE 6
The superimposition between pre- and post-molecular dynamics structures, where lower root-mean-square deviations were found. The sky color indicates the pre-molecular dynamics structure, and the pink color indicates the post-molecular dynamics structure.
FIGURE 7
FIGURE 7
The surface view of the docked complex during the molecular dynamics simulation. Snapshots were taken at 25, 50, 75, and 100 ns for the medicagol and Mpro complex. The binding pose and positions of the ligands were remained rigid in different simulation time intervals.
FIGURE 8
FIGURE 8
The surface view and the binding pockets of the faradiol and Mpro complex, for which the 25, 50, 75, and 100 ns snapshots were taken. The ligand molecules and binding in the interacting pockets of the proteins were remained similar across different simulation time intervals.
FIGURE 9
FIGURE 9
The surface view of the docked flavanthrin and Mpro complex, shown as 25, 50, 75, and 100 ns snapshots. The binding pose and interactions were remained in the same binding pockets. The figure were generated from Pymol software package.
See this image and copyright information in PMC

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