Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
J Mol Model. 2011 May;17(5):1149-61. doi: 10.1007/s00894-010-0817-2. Epub 2010 Aug 5.
Structure-based 3D-QSAR approaches (CoMFA and CoMSIA) were applied to understand the structural requirements of the Cyclin-dependent kinase 5/p25 inhibitors. Cyclin-dependent kinase 5 (CDK5) is believed to play an important role in the development of the central nervous system during the process of mammalian embryogenesis. Genetic algorithm based docking program (GOLD) was successfully utilized to orient the compounds inside the binding pocket of the CDK5/p25 structure. The adapted alignment method with the suitable parameters resulted in a reliable model. Furthermore, the final model was robust enough to forecast the activities of test compounds, satisfactorily. The contour maps were produced around the functional groups to understand the SAR requirements. Moreover, we also investigate the structural attributes of the inhibitors which make them selective toward CDK5/p25 over its close counterpart, i.e., CDK2. The study could be helpful to rationalize the new compounds with better inhibition and selectivity profiles against CDK5/p25.
基于结构的 3D-QSAR 方法（CoMFA 和 CoMSIA）被应用于理解细胞周期蛋白依赖性激酶 5/p25 抑制剂的结构要求。细胞周期蛋白依赖性激酶 5（CDK5）被认为在哺乳动物胚胎发生过程中中枢神经系统的发育中起着重要作用。基于遗传算法的对接程序（GOLD）成功地用于将化合物定向到 CDK5/p25 结构的结合口袋内。经过适当参数调整的适配对齐方法产生了可靠的模型。此外，最终模型足够稳健，可以令人满意地预测测试化合物的活性。在功能基团周围生成了等高线图，以了解 SAR 要求。此外，我们还研究了抑制剂的结构属性，这些属性使它们对 CDK5/p25 具有选择性，而不是对其密切对应的 CDK2。这项研究有助于合理化新化合物，使其对 CDK5/p25 具有更好的抑制和选择性。
