Institute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.
Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Australia.
Clin Exp Pharmacol Physiol. 2020 May;47(5):892-902. doi: 10.1111/1440-1681.13249. Epub 2020 Jan 24.
The single-strand human telomere overhang forms intramolecular high-order structures named G-quadruplex (G4) under physiological conditions. Telomere G4 stabilization prevents telomere lengthening by telomerase in cancer cells representing a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. We found that APC preferred the end-stacking binding with the telomere hybrid type II (hybrid-II) G4 as compared to the groove binding with the hybrid type I (hybrid-I) G4 remarkable stabilizing effect and more favourable binding free energies. Analysis of non-covalent interaction and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s. These findings provide evidence for the first time to shed light on the designs of selective telomere G4 stabilizers.
在生理条件下，单链人类端粒突出形成了称为 G-四链体（G4）的分子内高级结构。端粒 G4 的稳定化可防止端粒酶在癌细胞中端粒的延长，这代表了癌症治疗中的一种有前途的策略。本研究使用分子对接和分子动力学（MD）模拟，在原子水平上研究了阴离子酞菁 3,4',4'',4'''-四磺酸（APC）与人类杂交（3+1）G4s 的特异性结合。我们发现，与与杂交型 I（hybrid-I）G4 的沟结合相比，APC 更倾向于与端粒杂交型 II（hybrid-II）G4 的末端堆积结合，表现出显著的稳定化效果和更有利的结合自由能。非共价相互作用分析和结合自由能分解表明，范德华相互作用在 APC 与端粒杂交 G4 结合中起主导作用。这些发现首次为选择性端粒 G4 稳定剂的设计提供了证据。
