Prato Gary, Silvent Samantha, Saka Sammy, Lamberto Massimiliano, Kosenkov Dmytro
Department of Chemistry and Physics, Monmouth University , 400 Cedar Avenue, West Long Branch, New Jersey 07764, United States.
J Phys Chem B. 2015 Feb 26;119(8):3335-47. doi: 10.1021/jp509637y. Epub 2015 Feb 12.
Naphthalene diimide ligands have the potential to stabilize human telomeric G-quadruplex DNA via noncovalent interactions. Stabilization of G-quadruplex high order structures has become an important strategy to develop novel anticancer therapeutics. In this study four naphthalene diimide based ligands were analyzed in order to elucidate the principal factors determining contributions to G-quadruplex-ligand binding. Three possible modes of binding and their respective Gibbs free energies for two naphthalene diimide based di-N-alkylpyridinium substituted ligands have been determined using a molecular docking technique and compared to experimental results. The structures obtained from the molecular docking calculations, were analyzed using the ab initio based fragment molecular orbital (FMO) method in order to determine the major enthalpic contributions to the binding and types of interactions between the ligand and specific residues of the G-quadruplex. A computational methodology for the efficient and inexpensive ligand optimization as compared to fully ab initio methods based on the estimation of binding affinities of the naphthalene diimide derived ligands to G-quadruplex is proposed.
萘二亚胺配体有潜力通过非共价相互作用稳定人类端粒G-四链体DNA。稳定G-四链体高阶结构已成为开发新型抗癌疗法的重要策略。在本研究中，对四种基于萘二亚胺的配体进行了分析，以阐明决定G-四链体-配体结合贡献的主要因素。使用分子对接技术确定了两种基于萘二亚胺的二-N-烷基吡啶鎓取代配体的三种可能结合模式及其各自的吉布斯自由能，并与实验结果进行了比较。为了确定对结合的主要焓贡献以及配体与G-四链体特定残基之间的相互作用类型，使用基于从头算的片段分子轨道（FMO）方法对从分子对接计算中获得的结构进行了分析。与基于萘二亚胺衍生配体与G-四链体结合亲和力估计的完全从头算方法相比，提出了一种高效且廉价的配体优化计算方法。
