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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Binding of quinazolinones to c-KIT G-quadruplex; an interplay between hydrogen bonding and pi-pi stacking
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Binding of quinazolinones to c-KIT G-quadruplex; an interplay between hydrogen bonding and pi-pi stacking

机译：喹唑啉酮与C-kit G-quadruplex的结合; 氢键与PI-PI堆叠之间的相互作用

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摘要

Stabilization of G-quadruplex structures in the c-KIT promoter with the aid of ligands has become an area of great interest in potential cancer therapeutics. Understanding the binding process between ligands and G-quadruplex is essential for a discovery of selective ligands with high binding affinity to G-quadruplex. In the present work, binding mechanisms of 4-quinazolinones to c-KIT G-quadruplex were investigated theoretically by means of molecular dynamics (MD) simulations. To explore the binding affinity of ligands, binding free energy calculations were performed using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We demonstrate that the key interactions in G-quadruplex-ligand complexes are pi-pi stacking and hydrogen bond interactions. However, neither of these two interactions alone determines the stability of the G-quadruplex-ligand complexes; rather, it is the result of an intricate interplay between the two. To further examine the nature of the binding, a free energy decomposition analysis at residue level was carried out. The results clearly demonstrate the crucial roles of two hot spot residues (DG4 and DG8) for the binding of ligands to c-KIT G-quadruplex, and highlight the importance of the planar aromatic moiety of ligands in G-quadruplex stabilization via pi-pi stacking interactions. Our study can assist in the design of new derivatives of 4-quinazolinone with high binding affinity for c-KIT G-quadruplex.
机译：借助配体的C-kit启动子在C-kit启动子中的稳定化已成为潜在癌症治疗症的极大兴趣的领域。理解配体和G-四氢之间的结合过程对于发现具有高结合亲和力的选择性配体对G-QuadrapleS的选择性是必不可少的。在本作工作中，通过分子动力学（MD）模拟理论上研究了4-喹唑啉酮对C-kit G-Quadruplex的结合机制。为了探讨配体的结合亲和力，使用分子机械泊松 - 玻尔兹曼表面积（MM-PBSA）方法进行结合的自由能计算。我们证明G-Quadreple-Ligand复合物中的关键相互作用是PI-PI堆叠和氢键相互作用。然而，这些两种相互作用都不决定G-Quadreple-ligand复合物的稳定性;相反，这是两者之间复杂的相互作用的结果。为了进一步检查结合的性质，进行残留水平的自由能分解分析。结果清楚地证明了两个热点残基（DG4和DG8）对配体与C-KIT G-Quadreple的结合的关键作用，并突出了通过PI-PI在G-Quadreplex稳定中的平面芳族部分的重要性堆叠互动。我们的研究可以帮助设计4-喹唑啉酮的新衍生物，对C-kit G-QuadRuplex具有高结合亲和力。

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