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Chlordiazepoxide against signalling, receptor and regulatory proteins of breast cancer: a structure-based in-silico approach

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Abstract

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others. In this study, we included four crucial proteins that perform signalling, receptor, and regulatory action, namely- NUDIX Hydrolases, Dihydrofolate Reductase, HER2/neu Kinase and EGFR and performed multitargeted molecular docking studies against human-approved drugs using HTVS, SP and extra precise algorithms and filtered the poses with MM\GBSA, suggested a benzodiazepine derivative chlordiazepoxide, used as an anxiolytic agent, can be a multitargeted inhibitor with docking and MM\GBSA score ranging from − 4.628 to − 7.877 and − 18.59 to − 135.86 kcal/mol, respectively, and the most interacted residues were 6ARG, 6GLU, 3TRP, and 3VAL. The QikProp-based ADMET and DFT computations showed the suitability and stability of the drug candidate followed by 100 ns MD simulation in water and MMGBSA on trajectories, resulting in stable performance and many intermolecular interactions to make the complexes stable, which favours that chlordiazepoxide can be a multitargeted breast cancer inhibitor. However, experimental validation is needed before its use.

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Acknowledgements

The authors extend their appreciation to Taif University, Saudi Arabia, for supporting this work through project number (TU-DSPP-2024-13).

Funding

This research was funded by Taif University, Saudi Arabia with project No: TU-DSPP-2024-13.

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Authors and Affiliations

  1. Department of Clinical Laboratory Science, College of Applied Medical Science, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia

    Ahad Amer Alsaiari, Amal F. Gharib, Maha Mahfouz Bakhuraysah, Amani A. Alrehaili, Shatha M. Algethami, Hayfa Ali Alsaif & Norah Al Harthi

  2. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Al-Quwayiyah, Riyadh, 11433, Saudi Arabia

    Mohammed Ageeli Hakami

Authors
  1. Ahad Amer Alsaiari
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Contributions

Conceptualisation, funding, analysis, visualisation, writing the first draft, supervising the whole research project and refining the manuscript for publication; Ahad Amer Alsaiari. Conceptualisation, analysis, visualisation, writing the first draft; Amal F.Gharib. Data Collection, Analysis, visualisation, writing the first draft, extensive editing; Maha Mahfouz Bakhuraysah. Data preparation, processing, analysis, figure conversion and editing first draft; Amani A. Alrehaili. Reviewed and edited the manuscript and helped to revise; Shatha M.Algethami. Data Collection, Analysis, visualisation, writing the first draft, extensive editing; Hayfa Ali Alsaif. Data Collection, Analysis, visualisation, writing the first draft; Norah Al harthi. Conceptualisation, supervision, analysis, software, visualisation, writing and reviewing-editing the first draft; Mohammed Ageeli Hakami.

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Correspondence to Mohammed Ageeli Hakami.

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Alsaiari, A.A., Gharib, A.F., Bakhuraysah, M.M. et al. Chlordiazepoxide against signalling, receptor and regulatory proteins of breast cancer: a structure-based in-silico approach. Med Oncol 41, 117 (2024). https://doi.org/10.1007/s12032-024-02366-w

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