In silico discovery of potent inhibitors against monkeypox’s major structural proteins

Abstract

Monkeypox virus (MPXV) outbreak in non-endemic countries is a worldwide public health emergency. An enveloped double-stranded DNA virus belongs to the genus Orth poxvirus. A viral zoonotic infection known as monkeypox has been a serious risk to public health, especially in Africa. However, it has recently spread to other continents, so it might soon become a worldwide problem. There is an increased risk of transmission of the virus because there is a lack of effective treatment that cures the disease. To stop the multi-country outbreak from spreading, it is important to discover effective medications urgently. The objective of the current study is to swiftly find new treatments for the monkeypox virus using advanced computational approaches. By investigating five potential MPXV targets (DNA ligase, Palmytilated Extracellular Enveloped Virus (EEV) membrane protein, Scaffold protein D13, Thymidylate Kinase, and Viral core cysteine proteinase), this research was carried out using cutting-edge computational techniques against human monkeypox virus infection. Here we present the accurate 3D structures and their binding cavities of the selected targets with higher confidence using AlphaFold 2 and SiteMap analysis. Molecular docking and MD simulation analysis revealed the top five potential lead compounds with higher binding affinity and stability toward selected targets. Binding free energy calculations and other essential dynamics analysis supports the finding. The selected lead compounds utilizing virtual screening and drug repurposing approach reported in this study are beneficial for medical scientists and experimental biologists in drug development for the treatment of human MPXV.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human monkeypox virus
• antiviral
• drug repurposing
• drug design and development
• molecular docking
• molecular dynamics simulation
• mechanistic approach

Acknowledgments

The authors would like to acknowledge Shiv Nadar (Institution of Eminence Deemed to be University), Delhi-NCR, India for infrastructure support for the research work. Senior Research Fellowship awarded to Mr. Ashish Shrivastava (Project ID: 2021‐14351; File No.: BMI/11(100)/2022) by the Indian Council of Medical Research, New Delhi is also acknowledged. The authors also would like to acknowledge the support of Schrodinger and the team for providing an Evaluation License to our laboratory.

CRediT authorship contribution statement

Ashutosh Singh conceived, designed and analysed results of the study; Kiran Bharat Lokhande and Ashish Shrivastava performed the experiments, analyzed and interpreted the data; Kiran Bharat Lokhande, Ashish Shrivastava, and Ashutosh Singh validated the results; Kiran Bharat Lokhande and Ashish Shrivastava writing original draft; Ashutosh Singh and Kiran Bharat Lokhande reviewed the final version of the manuscript.

Disclosure statement

There is no conflict of interest declared by all authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.