New Insights into the Structures of Ligand-Quadruplex Complexes from Molecular Dynamics Simulations
New Insights into the Structures of Ligand-Quadruplex Complexes from Molecular Dynamics Simulations
复制标题
从分子动力学模拟对配体四联体复合物结构的新见解
DOI：
10.1021/jp106683n
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发表时间：
2010-11-25
影响因子：
3.3
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Hou, Jin-Qiang;Chen, Shuo-Bin;Huang, Zhi-Shu
g -四plex是由富含鸟嘌呤的序列形成的高阶DNA和RNA结构，它们是有吸引力的抗癌药物靶点。了解g -四重体及其配体在溶液中的三维相互作用是发现药物先导的关键。因此，从晶体学或核磁共振结构出发，对六种配体-四复体配合物进行了分子动力学研究。bracco -19、BSU6039、daunomycin、RHPS4、MMQ1和TMPyP4是研究中结合g -四联体结构的六种配体。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 -四重奏中移动，使配体在水溶液中与四重体结合。配体结合可以增加g -四重奏中胡格seen氢键的稳定性。然而，g -四重奏结合位点只能适合一个配体分子。配体可以在四联体的环或侧翼形成氢键。然而，并不是所有的相互作用都能稳定水溶液中的配体-四重络合物。这些发现有助于设计选择性和有效的g -四重体配体。
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.