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. 2023 Feb 1:13:1095068.
doi: 10.3389/fmicb.2022.1095068. eCollection 2022.

Identification of natural compounds as SARS-CoV-2 inhibitors via molecular docking and molecular dynamic simulation

Affiliations

Identification of natural compounds as SARS-CoV-2 inhibitors via molecular docking and molecular dynamic simulation

Tiantian Han et al. Front Microbiol. .

Abstract

Background: Base mutations increase the contagiousness and transmissibility of the Delta and Lambda strains and lead to the severity of the COVID-19 pandemic. Molecular docking and molecular dynamics (MD) simulations are frequently used for drug discovery and relocation. Small molecular compounds from Chinese herbs have an inhibitory effect on the virus. Therefore, this study used computational simulations to investigate the effects of small molecular compounds on the spike (S) protein and the binding between them and angiotensin-converting enzyme 2 (ACE2) receptors.

Methods: In this study, molecular docking, MD simulation, and protein-protein analysis were used to explore the medicinal target inhibition of Chinese herbal medicinal plant chemicals on SARS-CoV-2. 12,978 phytochemicals were screened against S proteins of SARS-CoV-2 Lambda and Delta mutants.

Results: Molecular docking showed that 65.61% and 65.28% of the compounds had the relatively stable binding ability to the S protein of Lambda and Delta mutants (docking score ≤ -6). The top five compounds with binding energy with Lambda and Delta mutants were clematichinenoside AR2 (-9.7), atratoglaucoside,b (-9.5), physalin b (-9.5), atratoglaucoside, a (-9.4), Ochnaflavone (-9.3) and neo-przewaquinone a (-10), Wikstrosin (-9.7), xilingsaponin A (-9.6), ardisianoside G (-9.6), and 23-epi-26-deoxyactein (-9.6), respectively. Four compounds (Casuarictin, Heterophylliin D, Protohypericin, and Glansrin B) could interact with S protein mutation sites of Lambda and Delta mutants, respectively, and MD simulation results showed that four plant chemicals and spike protein have good energy stable complex formation ability. In addition, protein-protein docking was carried out to evaluate the changes in ACE2 binding ability caused by the formation of four plant chemicals and S protein complexes. The analysis showed that the binding of four plant chemicals to the S protein could reduce the stability of the binding to ACE2, thereby reducing the replication ability of the virus.

Conclusion: To sum up, the study concluded that four phytochemicals (Casuarictin, Heterophylliin D, Protohypericin, and Glansrin B) had significant effects on the binding sites of the SARS-CoV-2 S protein. This study needs further in vitro and in vivo experimental validation of these major phytochemicals to assess their potential anti-SARS-CoV-2. Graphical abstract.

Keywords: Chinese herbal medicine; SARS-CoV-2 inhibitors; binding energy; molecular docking; molecular dynamics simulation.

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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

Graphical abstract
Graphical abstract
Figure 1
Figure 1
The CTD of S protein structure and evaluation. (A) The tertiary structure of CTD of S protein of Lambda and Delta strain. (B) The Ramachandran plot of the mutation S protein. The mutation residues were shown in orange and CTD of S protein was shown in palegreen.
Figure 2
Figure 2
Distribution bar graph of the affinity score of small molecular compounds with Lambda and Delta strain.
Figure 3
Figure 3
The top 10 conformations of the small molecule compounds bind to the Lambda strain mutation base. (A) Casuarictin. (B) C10230. (C) Periplocoside J. (D) Heterophylliin D. (E) Cyclopseudo-hypericin. (F) Glaucoside, d. (G) Hypericin. (H) β1-solamargine. (I) Mulberrofuran Q. (J) Atratoglaucoside, b.
Figure 4
Figure 4
The top 10 conformations of the small molecule compounds bind to the Delta strain mutation base. (A) Glansrin B. (B) Ardisiacrispin A. (C) Periplocoside J. (D) Cyclopseudo-hypericin. (E) Amentoflavone. (F) Ochnaflavone. (G) Hypericin. (H, I) Protohypericin. (J) Datuarmeteloside B. (K) Primulanin.
Figure 5
Figure 5
Molecular dynamics analysis of the top 2 conformations of small molecular compounds bind to mutation base. The results of protein RMSD, the RMSF of residue index and interactions fraction of Casuarictin (A, E, I), Heterophylliin D (B, F, J) Protohypericin (C, G, K) and Glansrin B (D, H, L) binds to the S-CTD of Lambda strain and Delta strain.
Figure 6
Figure 6
The cartoon, surface, and stick of Casuarictin (A), Heterophylliin D (B), Protohypericin (C), and Glansrin B (D) binding to S-CTD dock with ACE2 receptor. The small molecule compounds were shown in marine. The S-CTD of lambda and delta was shown in pale green. The residue of S-CTD was shown in split-pea. The ACE2 receptor was shown in light blue. The residue of the ACE2 receptor was shown in the slate. The hydrogen bonds were shown in red.

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