Hematopoietic cell kinase as a nexus for drug repurposing: implications for cancer and HIV therapy

Abstract

Hematopoietic cell kinase (HCK) has emerged as a potential target for therapeutic intervention in cancer and HIV infection because of its critical role in critical signaling pathways. Repurposing FDA-approved drugs offers an efficient strategy to identify new treatment options. Here, we address the need for novel therapies in cancer and HIV by investigating the potential of repurposed drugs against HCK. Our goal was to identify promising drug candidates with high binding affinities and specific interactions within the HCK binding pocket. We employed an integrated computational approach combining molecular docking and extensive molecular dynamics (MD) simulations. Initially, we analyzed the binding affinities and interaction patterns of a library of FDA-approved drugs sourced from DrugBank. After careful analysis, we focused on two compounds, Nilotinib and Radotinib, which exhibit exceptional binding affinities and specificity to the HCK binding pocket, including the active site. Additionally, we assessed the pharmacological properties of Nilotinib and Radotinib, making them attractive candidates for further drug development. Extensive all-atom MD simulations spanning 200 nanoseconds (ns) elucidated the conformational dynamics and stability of the HCK-Nilotinib and HCK-Radotinib complexes. These simulations demonstrate the robustness of these complexes over extended timescales. Our findings highlighted the potential of Nilotinib and Radotinib as promising candidates against HCK that offer valuable insights into their binding mechanisms. This computational approach provides a comprehensive understanding of drug interactions with HCK and sets the stage for future experimental validation and drug development endeavors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Hematopoietic cell kinase
• drug repurposing
• Nilotinib
• Radotinib
• virtual screening
• molecular dynamics simulation
• small molecule inhibitors

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the Large Research Groups Project under grant number (RGP.2/313/44).

Authors’ contributions

Conceptualization, M.A.A.A. and S.C.; methodology, S.W.; software, S.W. and S.C.; validation, M.A.A., S.W and A.A.; formal analysis, S.W.; investigation, S.W.; resources, A.A; data curation, S.W.; writing—original draft preparation, S.W. and A.A.; writing—review and editing, S.C. and A.A.; visualization, W.A; supervision, S.C; project administration, M.A.A.A; funding acquisition, S.W and A.A.; All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding authors.