靶向CDK6抗肿瘤小分子抑制剂的虚拟筛选

Virtual Screening of Antitumor Small Molecule Inhibitors Targeting CDK6

摘要: 目的：细胞周期蛋白依赖性激酶6 (Cyclin-dependent kinases 6, CDK6)过表达导致的细胞周期异常是导致癌细胞过度增殖的原因，阻断CDK6表达可抑制肿瘤存活和生长。因此，CDK6抑制剂被认为是一种很有前途的抗癌药物。运用不同的虚拟筛选方法，从Specs数据库中筛选具有CDK6抑制活性的成分。方法：在本研究中，设计了针对特定靶标CDK6的虚拟筛选流程。为了发现结构新颖的CDK6抑制剂，通过类药性评估、基于蛋白质–配体复合物的药效团搜索、分子对接技术等多轮虚拟筛选策略，从Specs数据库中寻找命中分子。结果：通过类药性初筛，共获得75,671个小分子。类药性化合物进行最佳药效团匹配得到630个小分子用于下一步的分子对接研究。最终保留了对接打分高于已知抑制剂且结合模式与已知抑制剂相似的2个小分子为最佳命中分子。结论：本研究为新一代CDK6抑制剂的开发提供研究方向。

Abstract: Objective: The abnormal cell cycle caused by Cyclin-dependent kinases 6 (CDK6) overexpression is responsible for excessive proliferation of cancer cells, and blocking CDK6 expression can inhibit tumor survival and growth. Therefore, CDK6 inhibitors are considered to be promising anticancer drugs. To screen the components withCDK6 inhibitory activity from the Specs database using dif-ferent virtual screening methods. Methods: In this study, a virtual screening process for CDK6 was designed. In order to discover CDK6 inhibitors with novel structures, multiple rounds of virtual screening strategies, such as drug-like evaluation, complex-based pharmacophore searching based on protein-ligand structure and molecular docking technology, were used to explore the hit mole-cules from Specs database. Result: A total of 75671 small molecules were obtained through the drug-like preliminary screening. Drug-like compounds were used to match the best receptor-ligand pharmacophore hypothesis, as a result, 630 common compounds were identified for further molecular docking. Finally, the two small molecules whose docking scores were higher than known inhibitors and binding patterns were similar to known inhibitors were retained as the best hit molecules. Conclusion: This study provides research direction for the development of a new generation of CDK6 inhibitors.