As the major structural component of microtubules, tubulin is an interesting target for the development of anticancer agents. In this study, 64 tubulin polymerization inhibitors of five-membered heterocycle-based combretastatin A-4 analogues were studied by a combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were established with desirable statistical parameters and excellent predictive ability. 20 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. Combining the binding free energy calculations and 3D-QSAR results, some new heterocycle-based combretastatin A-4 analogues were designed. Three of them were synthesized and biologically evaluated. Compound 13a displayed potent antiproliferative activity (IC₅₀ value of 1.31 μM against HepG2 cells, IC₅₀ value of 1.37 μM against A549 cells) and inhibition of tubulin polymerization activity (IC₅₀ value of 0.86 μM). Compound 13b also presented good activity against HepG2 cells (IC₅₀ value of 4.75 μM). The experimental results demonstrated that the built models were effective for the development of novel anticancer agents and tubulin inhibitors.

中文翻译：

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康布雷他汀A-4类似物作为抗癌药和微管蛋白抑制剂的分子模型研究，合成和生物学评估†

作为微管的主要结构成分，微管蛋白是抗癌药开发的有趣目标。在这项研究中，通过分子建模技术（包括3D-QSAR，分子对接和分子动力学（MD）模拟）的组合研究了五元杂环基康他汀A-4类似物的64种微管蛋白聚合抑制剂。建立了具有理想统计参数和出色预测能力的CoMFA（比较分子场分析）和CoMSIA（比较分子相似性指数分析）模型。成功进行了20 ns的MD模拟，以确认详细的绑定模式并验证对接结果的合理性。结合结合自由能计算和3D-QSAR结果，设计了一些新的基于杂环的康布雷他汀A-4类似物。其中三个被合成并进行了生物学评估。化合物图13A显示强效的抗增殖活性（IC ₅₀ 1.31μM的对HepG2细胞，IC值₅₀和微管蛋白聚合活性的抑制1.37μM的针对A549细胞的值）（IC ₅₀ 0.86μM的值）。化合物13b还表现出对HepG2细胞的良好活性（IC ₅₀值为4.75μM）。实验结果表明，所建立的模型对于开发新型抗癌药和微管蛋白抑制剂是有效的。