Almoyad Mohammad Ali Abdullah, Alsayari Abdulrhman, Wahab Shadma, Chandra Subhash
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Khamis Mushyt, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, King Khalid University, Saudi Arabia.
J Biomol Struct Dyn. 2024 Mar 26:1-11. doi: 10.1080/07391102.2024.2331092.
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.
造血细胞激酶（HCK）因其在关键信号通路中的关键作用，已成为癌症和HIV感染治疗干预的潜在靶点。重新利用美国食品药品监督管理局（FDA）批准的药物提供了一种识别新治疗方案的有效策略。在此，我们通过研究重新利用的药物针对HCK的潜力，来满足癌症和HIV领域对新型疗法的需求。我们的目标是识别出在HCK结合口袋内具有高结合亲和力和特异性相互作用的有前景的候选药物。我们采用了一种综合计算方法，结合分子对接和广泛的分子动力学（MD）模拟。最初，我们分析了来自DrugBank的FDA批准药物库的结合亲和力和相互作用模式。经过仔细分析，我们聚焦于两种化合物，尼罗替尼和拉多替尼，它们对HCK结合口袋（包括活性位点）表现出卓越的结合亲和力和特异性。此外，我们评估了尼罗替尼和拉多替尼的药理特性，使其成为进一步药物开发的有吸引力的候选物。长达200纳秒（ns）的广泛全原子MD模拟阐明了HCK - 尼罗替尼和HCK - 拉多替尼复合物的构象动力学和稳定性。这些模拟证明了这些复合物在延长时间尺度上的稳健性。我们的研究结果突出了尼罗替尼和拉多替尼作为针对HCK的有前景候选物的潜力，为它们的结合机制提供了有价值的见解。这种计算方法全面理解了药物与HCK的相互作用，为未来的实验验证和药物开发努力奠定了基础。
