Khater Ibrahim, Nassar Aaya
Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
PLoS One. 2025 Aug 22;20(8):e0330102. doi: 10.1371/journal.pone.0330102. eCollection 2025.
Dysregulation of the cyclin D/CDK complex is a common feature in various cancers, including colorectal, breast, and melanoma, leading to uncontrolled tumor growth and cell cycle progression. Targeting this complex has become a compelling therapeutic approach in oncology. FDA-approved CDK4/6 inhibitors, such as ribociclib, palbociclib, and abemaciclib, have demonstrated clinical efficacy, significantly improving patient outcomes. However, the development of resistance to these therapies emphasizes the urgent need for alternative strategies to overcome therapeutic limitations. The current study explores the potential of new inhibitors targeting the cyclin D/CDK axis by using virtual screening and molecular dynamics simulations. We conducted a virtual screening of the Zinc and PubChem databases, by utilizing a pharmacophore model generated by PocketQuery, to identify new candidate inhibitors of the cyclin D/CDK4 complex. The findings offer promising leads for further optimization, potentially paving the way for developing more effective treatments that circumvent resistance mechanisms and expand therapeutic options for cancer patients. Further experimental validation and in vivo studies are necessary to confirm the efficacy of these candidates and translate them into viable clinical treatments.
细胞周期蛋白D/细胞周期蛋白依赖性激酶（CDK）复合物的失调是包括结直肠癌、乳腺癌和黑色素瘤在内的各种癌症的共同特征，导致肿瘤生长失控和细胞周期进程。针对这一复合物已成为肿瘤学中一种引人注目的治疗方法。美国食品药品监督管理局（FDA）批准的CDK4/6抑制剂，如瑞博西尼、哌柏西利和阿贝西利，已显示出临床疗效，显著改善了患者的预后。然而，对这些疗法产生耐药性凸显了迫切需要替代策略来克服治疗局限性。当前的研究通过虚拟筛选和分子动力学模拟探索了靶向细胞周期蛋白D/CDK轴的新抑制剂的潜力。我们利用PocketQuery生成的药效团模型对锌数据库和PubChem数据库进行了虚拟筛选，以识别细胞周期蛋白D/CDK4复合物的新候选抑制剂。这些发现为进一步优化提供了有希望的线索，有可能为开发更有效的治疗方法铺平道路，这些治疗方法可规避耐药机制并为癌症患者扩大治疗选择。需要进一步的实验验证和体内研究来确认这些候选药物的疗效，并将它们转化为可行的临床治疗方法。
