School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
J Comput Aided Mol Des. 2012 Dec;26(12):1355-68. doi: 10.1007/s10822-012-9619-1. Epub 2012 Dec 13.
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.
G-四链体是由富含鸟嘌呤的序列形成的高级 DNA 和 RNA 结构。这些结构最近已成为一类新的潜在抗癌药物分子靶标。理解小分子配体与其在溶液中的 G-四链体靶标之间的三维相互作用对于合理的药物设计和有效优化 G-四链体配体至关重要。迄今为止，合理的配体设计主要集中在 G-四聚体平台上。值得注意的是，正如晶体学研究中观察到的那样，小分子也可以与环核苷酸结合。因此，阐明不同结合模式的配体如何影响 G-四链体的灵活性的机制将是很有趣的。在本研究中，基于晶体结构分析，构建了与端粒 G-四链体以不同模式结合的四取代萘二酰亚胺配体的模型，并通过分子动力学模拟方法对其进行了模拟。通过一系列计算分析，研究了配体-四链体复合物的结构、动力学和相互作用。我们的结果表明，配体与环的结合在水溶液中是可行的，但取决于环的特定排列。配体与环的结合增强了 G-四链体的灵活性，而配体同时与四聚体和环的结合则降低了其灵活性。这些结果增加了我们对具有不同结合模式的配体对 G-四链体灵活性的影响的理解。这种理解将有助于合理设计更具选择性和更有效的 G-四链体结合配体。
