School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
J Phys Chem B. 2010 Nov 25;114(46):15301-10. doi: 10.1021/jp106683n. Epub 2010 Nov 4.
G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences, and they are attractive anticancer drug targets. Understanding the three-dimensional interactions between a G-quadruplex and its ligand in solution is the key to discovering a drug lead. Hence, from crystallographic or NMR structures, molecular dynamics studies have been performed on six ligand-quadruplex complexes. BRACO-19, BSU6039, daunomycin, RHPS4, MMQ1, and TMPyP4 are the six ligands that bind to the G-quadruplex structures in the studies. Based on molecular dynamics simulations and a series of computational analyses, the results suggest that ions move away from the external G-quartet to let the ligand bind to the quadruplex in aqueous solution. The ligand binding can increase the stability of the Hoogseen hydrogen bonds within the G-quartet. However, the G-quartet binding site can only fit one ligand molecule. The ligand can form hydrogen bonds at the loop or flank of the quadruplex. However, not all the interactions will stabilize the ligand-quadruplex complex in aqueous solution. These findings can assist in the design of selective and potent G-quadruplex ligands.
四链体是由富含鸟嘌呤的序列形成的高级 DNA 和 RNA 结构，它们是有吸引力的抗癌药物靶点。了解 G-四链体与其配体在溶液中的三维相互作用是发现药物先导物的关键。因此，已经对六个配体-四链体复合物的晶体学或 NMR 结构进行了分子动力学研究。BRACO-19、BSU6039、柔红霉素、RHPS4、MMQ1 和 TMPyP4 是在研究中与 G-四链体结构结合的六种配体。基于分子动力学模拟和一系列计算分析，结果表明离子从外部 G-四重奏中移出，让配体在水溶液中与四链体结合。配体结合可以增加 G-四重奏内 Hoogseen 氢键的稳定性。然而，G-四重奏结合位点只能容纳一个配体分子。配体可以在四链体的环或侧翼形成氢键。然而，并非所有的相互作用都能稳定配体-四链体复合物在水溶液中。这些发现可以帮助设计选择性和有效的 G-四链体配体。
