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. 2024 Sep;64(3):1057-1074.
doi: 10.1007/s12088-024-01244-3. Epub 2024 Mar 28.

Inhibition of Monkeypox Virus DNA Polymerase Using Moringa oleifera Phytochemicals: Computational Studies of Drug-Likeness, Molecular Docking, Molecular Dynamics Simulation and Density Functional Theory

Affiliations

Inhibition of Monkeypox Virus DNA Polymerase Using Moringa oleifera Phytochemicals: Computational Studies of Drug-Likeness, Molecular Docking, Molecular Dynamics Simulation and Density Functional Theory

Muhammad Abrar Yousaf et al. Indian J Microbiol. 2024 Sep.

Abstract

The emergence of zoonotic monkeypox (MPX) disease, caused by the double-stranded DNA monkeypox virus (MPXV), has become a global threat. Due to unavailability of a specific small molecule drug for MPX, this study investigated Moringa oleifera phytochemicals to find potent and safe inhibitors of DNA Polymerase (DNA Pol), a poxvirus drug target due to its role in the viral life cycle. For that, 146 phytochemicals were screened through drug-likeness and molecular docking analyses. Among these, 136 compounds exhibited drug-like properties, with Gossypetin showing the highest binding affinity (- 7.8 kcal/mol), followed by Riboflavin (- 7.6 kcal/mol) and Ellagic acid (- 7.6 kcal/mol). In comparison, the control drugs Cidofovir and Brincidofovir displayed lower binding affinities, with binding energies of - 6.0 kcal/mol and - 5.1 kcal/mol, respectively. Hydrogen bonds, electrostatic and hydrophobic interactions were the main non-bond interactions between inhibitors and protein active site. The identified compounds were further evaluated using molecular dynamics simulation, density functional theory analysis and ADMET analysis. Molecular dynamics simulations conducted over 200 ns revealed that DNA Pol-Gossypetin complex was not stable, however, Riboflavin and Ellagic acid complexes showed excellent stability indicating them as better DNA Pol inhibitors. The density functional theory analysis exhibited the chemical reactivity of these inhibitor compounds. The ADMET analysis suggested that the top phytochemicals were safe and showed no toxicity. In conclusion, this study has identified Riboflavin and Ellagic acid as potential DNA Pol inhibitors to control MPXV. Further experimental assays and clinical trials are needed to confirm their activity against the disease.

Keywords: DNA Polymerase; Density functional theory; Molecular docking; Molecular dynamics simulation; Monkeypox virus.

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Conflict of interest statement

Conflict of interestThe authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The drug-likeness properties of Lipinski's rule of five are determined by four parameters, namely A molecular weight, B MLogP, C number of hydrogen bond acceptors and D number of hydrogen bond donors. E Out of the 146 phytochemicals present in M. oleifera, 136 compounds exhibited either zero or one violation, while F demonstrating drug-like properties
Fig. 2
Fig. 2
Holoenzyme-DNA complex (PDB ID: 8HG1) containing DNA Pol F8, processivity factors (A22 and E4), primer-template DNA, thymidine-5′-triphosphate (TTP) substrate and a magnesium ion (Mg+2) as a catalytic ion. Interactions of TTP with the complex have also been shown
Fig. 3
Fig. 3
Molecular docking analysis of Gossypetin (PubChem CID: 5,280,647) with the MPXV DNA Pol. A Two-dimensional interactions of Gossypetin with the active site residues of DNA Pol. B Three-dimensional interactions of Gossypetin with the active site residues of DNA Pol. C Interactions of Gossypetin in the binding pocket of DNA Pol
Fig. 4
Fig. 4
Molecular docking analysis of Riboflavin (PubChem CID: 493,570) with the MPXV DNA Pol. A Two-dimensional interactions of Riboflavin with the active site residues of DNA Pol. B Three-dimensional interactions of Riboflavin with the active site residues of DNA Pol. C Interactions of Riboflavin in the binding pocket of DNA Pol
Fig. 5
Fig. 5
Molecular docking analysis of Ellagic acid (PubChem CID: 5,281,855) with the MPXV DNA Pol. A Two-dimensional interactions of Ellagic acid with the active site residues of DNA Pol. B Three-dimensional interactions of Ellagic acid with the active site residues of DNA Pol. C Interactions of Ellagic acid in the binding pocket of DNA Pol
Fig. 6
Fig. 6
Two-dimensional interactions of control drugs, Cidofovir (A) and Brincidofovir (B) with the active site residues of DNA Pol analyzed by molecular docking analysis
Fig. 7
Fig. 7
The root mean square deviation (RMSD) profile of native MPXV DNA Pol protein and protein complex with Gossypetin, Riboflavin and Ellagic acid during the 200 ns period of molecular dynamics simulation
Fig. 8
Fig. 8
The root mean square fluctuation (RMSF) profile of native MPXV DNA Pol protein and protein complex with Gossypetin, Riboflavin and Ellagic acid during the 200 ns period of molecular dynamics simulation
Fig. 9
Fig. 9
The radius of gyration (Rg) profile of native MPXV DNA Pol protein and protein complex with Gossypetin, Riboflavin and Ellagic acid during the 200 ns period of molecular dynamics simulation
Fig. 10
Fig. 10
The solvent accessible surface area (SASA) profile of native MPXV DNA Pol protein and protein complex with Gossypetin, Riboflavin and Ellagic acid during the 200 ns period of molecular dynamics simulation
Fig. 11
Fig. 11
Energy level diagram with molecular orbitals spatial distribution of A Gossypetin, B Riboflavin and C Ellagic acid

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