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Identification of novel potential inhibitors of monkeypox virus thymidine kinase using molecular docking, molecular dynamics simulation and MM/PBSA methods

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Abstract

The monkeypox spread has been announced a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). Both monkeypox and smallpox viruses are placed in the genus Orthopoxvirus. Despite recommendations for the administration of smallpox drugs versus monkeypox, no specific drug for monkeypox has yet been introduced. A reliable and effective method against this outbreak can be the use of natural products. This study aimed for identification of natural flavonoid derivatives as potential thymidine kinase inhibitors, the main drug target of monkeypox virus. Thymidine kinase protein structure was predicted by homology modeling and the quality of generated model was evaluated. Then, the interaction between natural flavonoids and the modeled thymidine kinase was explored by molecular docking. Based on docking results, more than half of the flavonoids with higher docking scores compared to reference drug (ganciclovir) were exhibited better binding affinities toward the protein. In addition, stability of the top flavonoids including eupatorin, fisetin, rhamnetin and scutellarein, was confirmed by MD simulations and binding free energy calculations using MM/PBSA analysis. These selected compounds were also shown acceptable results for drug likeness and ADMET analysis. Therefore, the results of the study showed that these flavonoids could be considered as potential thymidine kinase inhibitors for use against monkeypox virus.

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Abbreviations

MPXV:

Human Monkeypox Virus

WHO:

World Health Organization

MD:

Molecular dynamics

GROMACS:

GROningenMaChine for chemical simulations

RMSD:

Root-mean-square deviation

PDB:

Protein data bank

Rg:

Radius of gyration

RMSF:

Root-mean-square fluctuation

MM/PBSA:

Molecular mechanic/Poisson–Boltzmann surface Area

SPC:

Simple point charge

SASA:

Solvent accessible surface area

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Acknowledgements

We are grateful to Clinical Biochemistry Research Center, Basic Health Sciences Institute; Shahrekord University of Medical Sciences for supporting this work by grant code 3961.

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  1. Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Tooba Abdizadeh

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Tooba Abdizadeh wrote the main manuscript text and prepared figures and reviewed the manuscript.

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Abdizadeh, T. Identification of novel potential inhibitors of monkeypox virus thymidine kinase using molecular docking, molecular dynamics simulation and MM/PBSA methods. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10692-w

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