The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (e.g., PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex–duplex hybrid. The structures indicate that the rigid aromatic rings of PyPDS/PDS linked by flexible amide bonds match adaptively with G-tetrad planes, enhancing π–π stacking and achieving specific recognition of G4s. The aliphatic amine side chains of PyPDS/PDS adjust conformation to interact with the phosphate backbone via hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N–H of PyPDS/PDS amide bonds interacts with two O₆s of G-tetrad guanines via hydrogen bonding, achieving a further increase in affinity for G4s, which is different from most G4 ligands. Our findings reveal from structural perspectives that the rational assembly of rigid and flexible structural units in a ligand can synergistically improve the selectivity and affinity for G4s through spatial selective and adaptive matching.

中文翻译：

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Pyridostatin 及其与 G-四链体特异性结合的衍生物的结构基础

核酸 G-四链体 (G4) 已成为癌症和神经退行性疾病等多种疾病的有希望的治疗靶点。在小分子 G4 结合剂中，pyridostatin (PDS) 及其衍生物 (例如PyPDS) 对 G4 表现出高度特异性，但它们特异性识别 G4 的结构基础仍然未知。在这里，我们提出了 PyPDS 和 PDS 的两种解决方案结构，具有四重-双重混合。结构表明，通过柔性酰胺键连接的 PyPDS/PDS 的刚性芳环与 G-四联体平面自适应匹配，增强了 π-π 堆叠并实现了对 G4s 的特异性识别。PyPDS/PDS 的脂肪胺侧链通过调节构象与磷酸骨架相互作用氢键和静电相互作用，增加对 G4 的亲和力。此外，PyPDS/PDS 酰胺键的 N-H通过氢键与 G-四联体鸟嘌呤的两个 O ₆ s 相互作用，进一步提高了对 G4s 的亲和力，这与大多数 G4 配体不同。我们的研究结果从结构的角度揭示了配体中刚性和柔性结构单元的合理组装可以通过空间选择性和自适应匹配协同提高对 G4 的选择性和亲和力。