Abstract

Excessive cell proliferation due to cell cycle disorders is one of the hallmarks of breast cancer. Cyclin-dependent kinases (CDKs), which are involved in the transition of the cell cycle from G1 phase to S phase by combining CDKs with cyclin, are considered promising targets with broad therapeutic potential based on their critical role in cell cycle regulation. Pharmacological evidence has shown that abnormal cell cycle due to the overexpression of CDK6 is responsible for the hyperproliferation of cancer cells. Blocking CDK6 expression inhibits tumour survival and growth. Therefore, CDK6 can be regarded as a potential target for anticancer therapeutics. Thus, small molecules that can be considered CDK inhibitors have been developed into promising anticancer drugs. In this study, combined structure-based and ligand-based in silicon models were created to identify new chemical entities against CDK6 with the appropriate pharmacokinetic properties. The database used to screen drug-like compounds in this thesis was based on the best E-pharmacophore hypothesis and the best ligand-based drug hypothesis. As a result, 147 common compounds were identified by further molecular docking. Surprisingly, the in vitro evaluation results of 20 of those compounds showed that the two had good CDK6 inhibitory effects. The best compound was subjected to kinase panel screening, followed by molecular dynamic simulations. The 50-ns MD studies revealed the pivotal role of VAL101 in the binding of inhibitors to CDK6. Overall, the identification of two new chemical entities with CDK6 inhibitory activity demonstrated the feasibility and potential of the new method.

Graphic abstract

中文翻译：

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通过计算方法发现新的小分子细胞周期蛋白依赖性激酶 6 抑制剂。

摘要

由于细胞周期紊乱导致的过度细胞增殖是乳腺癌的标志之一。细胞周期蛋白依赖性激酶 (CDKs) 通过将 CDK 与细胞周期蛋白结合参与细胞周期从 G1 期到 S 期的转变，因其在细胞周期调节中的关键作用而被认为具有广泛的治疗潜力。药理学证据表明，由于 CDK6 过表达导致的异常细胞周期是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 可被视为抗癌治疗的潜在靶点。因此，可以被认为是 CDK 抑制剂的小分子已被开发成有前景的抗癌药物。在本研究中，结合基于结构和基于配体的在硅模型中创建了具有适当药代动力学特性的针对 CDK6 的新化学实体。本论文中用于筛选类药化合物的数据库是基于最佳E-药效团假设和最佳配体药物假设。结果，通过进一步的分子对接鉴定了 147 种常见化合物。令人惊讶的是，其中 20 种化合物的体外评价结果表明，这两种化合物具有良好的 CDK6 抑制作用。对最佳化合物进行激酶组筛选，然后进行分子动力学模拟。50 ns MD 研究揭示了 VAL101 在抑制剂与 CDK6 结合中的关键作用。总的来说，鉴定出两种具有 CDK6 抑制活性的新化学实体证明了新方法的可行性和潜力。

图形摘要