Tepotinib and tivantinib as potential inhibitors for the serine/threonine kinase of the mpox virus: insights from structural bioinformatics analysis

Abstract

The serine/threonine kinase (STK) plays a central role as the primary kinase in poxviruses, directing phosphoryl transfer reactions. Such reactions are pivotal for the activation of certain proteins during viral replication, assembly, and maturation. Therefore, targeting this key protein is anticipated to impede virus replication. In this work, a structural bioinformatics approach was employed to evaluate the potential of drug-like kinase inhibitors in binding to the ATP-binding pocket on the STK of the Mpox virus. Virtual screening of known kinase inhibitors revealed that the top 10 inhibitors exhibited binding affinities ranging from −8.59 to −12.05 kcal/mol. The rescoring of compounds using the deep-learning default model in GNINA was performed to predict accurate binding poses. Subsequently, the top three inhibitors underwent unbiased molecular dynamics (MD) simulations for 100 ns. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and Principal Component Analysis (PCA) suggested tepotinib as a competitive inhibitor for Mpox virus STK as evidenced by its binding free energy and the induction of similar conformational behavior of the enzyme. Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug repurposing
• kinase inhibitors
• MD simulations
• molecular docking
• MM/GBSA
• orthopoxvirus

Data availability statement

The data that support the findings of this study are available from the corresponding author, JMA, upon reasonable request.

Acknowledgments

We would like to express our gratitude to Bibliotheca Alexandrina for providing access to their High-Performance Computing facility.

Disclosure statement

There are no conflicts of interest regarding this paper or its publication.

Author contributions

JMA conceptualized and designed the study, performed modeling and calculations, analyzed the data, and wrote the manuscript. AAE & MMA supervised the study and contributed to proofreading the final manuscript.

Additional information

Funding

The work did not receive any specific grant from any funding sources.