Yang Dah-Yen, Chang Ta-Chau, Sheu Sheh-Yi
Department of Life Sciences and Institute of Genome Sciences, Institute of Bioinformatics, and Structural Biology Program, National Yang-Ming University, Taipei 112, Taiwan.
J Phys Chem A. 2007 Sep 27;111(38):9224-32. doi: 10.1021/jp071963o. Epub 2007 Jul 14.
The mechanism of inhibition of telomerase by drugs is a key factor in an understanding of guanine-quadruplex complex stabilization during human cancer. This study describes a simulated annealing docking and molecular dynamics simulation to investigate a synthesized potent inhibitor, 3,6-bis(1-methyl-4-vinylpyridinium iodine) carbazole (BMVC), which stabilizes the quadruplex structure of the human telomeric DNA sequence d[AG3(T(2)AG(3))3] and inhibits telomerase activity. The compound was predicted to selectively interact with the quadruplex structure. During our simulation, the binding affinities were calculated and used to predict the best drug-binding sites as well as enhanced selectivity compared with other compounds. Our studies suggest that the simulation results quite coincide with the experimental results. In addition, molecular modeling shows that a 2:1 binding model involving the external binding of BMVC to both ends of the G-quartet of d[AG(3)(T(2)AG)3))3] is the most stable binding mode and this agrees with the absorbance titration results that show two binding sites. Of particular interest is that one pyridinium ring and carbazole moiety of the BMVC can stack well at the end of G-quartet. This implies that BMVC is a good human quadruplex stabilizer and also a good telomerase inhibitor.
药物抑制端粒酶的机制是理解人类癌症期间鸟嘌呤四链体复合物稳定性的关键因素。本研究描述了一种模拟退火对接和分子动力学模拟，以研究一种合成的强效抑制剂3,6-双(1-甲基-4-乙烯基吡啶碘)咔唑(BMVC)，它能稳定人类端粒DNA序列d[AG3(T(2)AG(3))3]的四链体结构并抑制端粒酶活性。预测该化合物与四链体结构选择性相互作用。在我们的模拟过程中，计算了结合亲和力，并用于预测最佳药物结合位点以及与其他化合物相比增强的选择性。我们的研究表明模拟结果与实验结果相当吻合。此外，分子建模显示，一种涉及BMVC与d[AG(3)(T(2)AG)3))3]的G-四重体两端外部结合的2:1结合模型是最稳定的结合模式，这与显示两个结合位点的吸光度滴定结果一致。特别有趣的是，BMVC的一个吡啶鎓环和咔唑部分可以很好地堆积在G-四重体的末端。这意味着BMVC是一种良好的人类四链体稳定剂，也是一种良好的端粒酶抑制剂。
