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image of Leveraging Tubulin Isotype Structural Differences to Design Less Hematotoxic β5 Selective Covalent Inhibitors for NSCLC

Abstract

Aim

This study aims to discover and design β-5 tubulin-specific covalent inhibitors for non-small cell lung cancer (NSCLC) that can minimize hematotoxicity, a major side effect of current microtubule-targeting agents (MTAs).

Background

Current microtubule-targeting drugs cause toxicities such as hematotoxicity and multidrug resistance (MDR). The colchicine binding site in β-5 has Cys-239, whereas β-1 has Ser-239, allowing selective inhibition based on the reactivity differences for covalent reactions.

Methods

β-5 and β-1 tubulin models were developed, and covalent docking and virtual screening were conducted to identify selective inhibitors targeting the β-5 tubulin colchicine binding site. Twenty hits were selected, and a comparative study was carried out between β-5 and β-1 to evaluate the selectivity and binding potential of the inhibitors.

Results

Among the 20 identified hits, four compounds demonstrated selective inhibition of β-5 tubulin, exhibiting stronger binding affinity for β-5 over β-1 tubulin. Molecular dynamics studies further confirmed their stability and enhanced binding, highlighting their potential as promising candidates for further drug development.

Conclusion

The study identified four novel β-5 tubulin-specific covalent inhibitors that may act as potential therapeutic agents for NSCLC, with the possibility of reduced hematotoxicity. These findings suggest that selective inhibition could help minimize side effects, addressing a critical need in cancer treatment.

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2025-07-02
2025-09-13

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Leveraging Tubulin Isotype Structural Differences to Design Less Hematotoxic β5 Selective Covalent Inhibitors for NSCLC
Bentham Science Publishers ; https://doi.org/10.2174/0115680266367194250619053553
/content/journals/ctmc/10.2174/0115680266367194250619053553
/content/journals/ctmc/10.2174/0115680266367194250619053553
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  • Article Type:     Research Article
Keywords: Covalent docking ; MD simulation ; NSCLC ; hematotoxicity ; Selective inhibition ; colchicine binding site

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