Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus

Amar Ajmal; Arif Mahmood; Chandni Hayat; Mohammed Ageeli Hakami; Bader S Alotaibi; Muhammad Umair; Ashraf N Abdalla; Ping Li; Pei He; Abdul Wadood; Junjian Hu

doi:10.3389/fcimb.2023.1159389

Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus

Front Cell Infect Microbiol. 2023 May 29:13:1159389. doi: 10.3389/fcimb.2023.1159389. eCollection 2023.

Authors

Affiliations

¹ Department of Biochemistry, Computational Medicinal Chemistry Laboratory, Abdul Wali Khan University, Mardan, Pakistan.
² Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
³ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al-Quwayiyah, Shaqra University, Riyadh, Saudi Arabia.
⁴ Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan.
⁵ Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁶ Institute of Biomedical Sciences, Shanxi University, Taiyuan, China.
⁷ Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁸ Department of Central Laboratory, SSL Central Hospital of Dongguan City, Affiliated Dongguan Shilong People's Hospital of Southern Medical University, Dongguan, China.

Abstract

Introduction: Monkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus.

Methods: In our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation.

Results: Based on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds-DB16335, DB15796, and DB16250 -along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase.

Discussion: Additionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds.

Keywords: MD simulation; drugs development; homology modeling; molecular docking; monkeypox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computers
Drug Repositioning
Humans
Molecular Docking Simulation
Monkeypox virus*
Mpox (monkeypox)*

Substances

dTMP kinase

Grants and funding

The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: 23UQU4331128DSR001. This study is also funded by the Incubation Fund of SSL Central Hospital of Dongguan (YJ002).