Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Avenue, West Lafayette, Indiana 47904, United States.
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
J Med Chem. 2021 Nov 11;64(21):16205-16212. doi: 10.1021/acs.jmedchem.1c01508. Epub 2021 Oct 22.
The medicinal natural product berberine is one of the most actively studied and pursued G-quadruplex (G4)-ligands. The major G-quadruplex formed in the promoter region of the MYC oncogene (MycG4) is an attractive drug target and a prominent example and model structure for parallel G-quadruplexes. G4-targeted berberine derivatives have been actively developed; however, the analogue design was based on a previous crystal structure in which berberine binds as a dimer to a parallel G-quadruplex. Herein, we show that in solution, the binding mode and stoichiometry of berberine are substantially different from the crystal structure: berberine binds as a monomer to MycG4 using a base-recruitment mechanism with a reversed orientation in that the positively charged convex side is actually positioned above the tetrad center. Our structure provides a physiologically relevant basis for the future structure-based rational design of G4-targeted berberine derivatives, and this study demonstrates that it is crucial to validate the ligand-DNA interactions.
药用天然产物小檗碱是研究和应用最广泛的 G-四链体 (G4) 配体之一。在 MYC 癌基因启动子区形成的主要 G-四链体 (MycG4) 是一个有吸引力的药物靶点，也是平行 G-四链体的突出范例和模型结构。已经积极开发了靶向 G4 的小檗碱衍生物；然而，类似物的设计基于之前的晶体结构，其中小檗碱作为二聚体结合到平行 G-四链体上。本文表明，在溶液中，小檗碱的结合模式和化学计量与晶体结构有很大的不同：小檗碱通过碱基募集机制以单体形式与 MycG4 结合，其方向相反，即带正电荷的凸面实际上位于四联体中心之上。我们的结构为基于结构的 G4 靶向小檗碱衍生物的合理设计提供了生理相关的基础，本研究表明验证配体-DNA 相互作用至关重要。
