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Rare deleterious mutations in Bruton’s tyrosine kinase as biomarkers for ibrutinib-based therapy: an in silico insight

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Abstract

Context

Squamous cell carcinoma (SCC) is the second most common type of skin cancer caused by malignant keratinocytes. Multiple studies have shown that protein mutations have a significant impact on the development and progression of cancer, including SCC. We attempted to decode the effect of single amino acid mutations in the Bruton’s tyrosine kinase (BTK) protein in this study. Molecular dynamic (MD) simulations were performed on selected deleterious mutations of the BTK protein, revealing that the variants adversely affect the protein, indicating that they may contribute to the prognosis of SCC by making the protein unstable. Then, we investigated the interaction between the protein and its mutants with ibrutinib, a drug designed to treat SCC. Even though the mutations have deleterious effects on protein structure, they bind to ibrutinib similarly to their wild type counterpart. This study demonstrates that the effect of detected missense mutations is unfavorable and can result in function loss, which is severe for SCC, but that ibrutinib-based therapy can still be effective on them, and the mutations can be used as biomarkers for Ibrutinib-based treatment.

Methods

Seven different computational techniques were used to compute the effect of SAVs in accordance with the experimental requirements of this study. To understand the differences in protein and mutant dynamics, MD simulation and trajectory analysis, including RMSD, RMSF, PCA, and contact analysis, were performed. The free binding energy and its decomposition for each protein-drug complex were determined using docking, MM-GBSA, MM-PBSA, and interaction analysis (wild and mutants).

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Data availability

The authors confirm that all the necessary data to replicate the results of this study is included in the manuscript.

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Authors and Affiliations

  1. Department of Biotechnology, Delhi Technological University, Delhi, 110042, India

    Jaishree Meena & Yasha Hasija

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  1. Jaishree Meena
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  2. Yasha Hasija
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Contributions

The study was conceived by Y.H. and J.M. performed computations. Y.H. supervised the findings of the work. Both the authors discussed the results and contributed to the final manuscript.

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Correspondence to Yasha Hasija.

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The study was done using only computational methods, no living samples were used; therefore, ethical approval is not applicable.

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Meena, J., Hasija, Y. Rare deleterious mutations in Bruton’s tyrosine kinase as biomarkers for ibrutinib-based therapy: an in silico insight. J Mol Model 29, 120 (2023). https://doi.org/10.1007/s00894-023-05515-6

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