7x2z

Publication Abstract from PubMed

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 pi-pi 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 O(6)s 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.

Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes.,Liu LY, Ma TZ, Zeng YL, Liu W, Mao ZW J Am Chem Soc. 2022 Jul 6;144(26):11878-11887. doi: 10.1021/jacs.2c04775. Epub , 2022 Jun 24. PMID:35749293^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.