The cyclin-dependent kinase 5 (CDK5) is an unusual member of the CDKs family due to its role in the central nervous system. The specific inhibition of cyclin-dependent kinase 5 (CDK5) is highly desirable in combating a wide range of conditions including neurodegenaration, cancer, and diabetes. In this study, we elucidated the potential of in-house developed plant-derived semi-synthetic (AAB) analogues to act as ATP competitive inhibitors to selectively inhibit CDK5. We integrated high-end computational approaches including explicit-solvent molecular dynamics (MD) simulations, steered MD simulations, and enhanced umbrella sampling simulations to rank and compare the AAB molecules with two selective CDK5 inhibitors (4a and Indolinone-A). Our results suggested high affinity of AAB scaffolds (AAB-6 and AAB-8) to selectively interact with the active site of CDK5. Simultaneously, both these molecules showed unfavorable binding free energies for CDK2, manifesting selectivity for CDK5 over CDK2. Moreover, we demonstrated the possible unbinding pathways of the top AAB analogues from the catalytic pocket of CDK5 and compared them with the standard molecules. The present computational approach could also be used to target critical proteins involved in various diseases.

由于其在中枢神经系统中的作用，细胞周期蛋白依赖性激酶 5 (CDK5) 是 CDKs 家族的一个不寻常成员。细胞周期蛋白依赖性激酶 5 (CDK5) 的特异性抑制在对抗包括神经退行性变、癌症和糖尿病在内的多种疾病方面是非常理想的。在这项研究中，我们阐明了内部开发的植物衍生半合成 (AAB) 类似物作为 ATP 竞争性抑制剂选择性抑制 CDK5 的潜力。我们集成了高端计算方法，包括显式溶剂分子动力学 (MD) 模拟、转向 MD 模拟和增强的伞状采样模拟，以对 AAB 分子与两种选择性 CDK5 抑制剂（4a 和 Indolinone-A）进行排序和比较。我们的结果表明 AAB 支架（AAB-6 和 AAB-8）具有高亲和力，可以选择性地与 CDK5 的活性位点相互作用。同时，这两种分子都显示出对 CDK2 不利的结合自由能，表现出对 CDK5 的选择性超过 CDK2。此外，我们展示了来自 CDK5 催化口袋的顶级 AAB 类似物的可能解结合途径，并将它们与标准分子进行了比较。本计算方法还可用于靶向涉及各种疾病的关键蛋白质。