Katzman Brooke M, Cox Bryan D, Prosser Anthony R, Alcaraz Ana A, Murat Brigitte, Héroux Madeleine, Tebben Andrew, Zhang Yong, Schroeder Gretchen M, Snyder James P, Wilson Lawrence J, Liotta Dennis C
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
Medicinal Chemistry platform, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec H3C 3J7, Canada.
ACS Med Chem Lett. 2018 Nov 30;10(1):67-73. doi: 10.1021/acsmedchemlett.8b00441. eCollection 2019 Jan 10.
The rationale for the structural and mechanistic basis of a tetrahydroisoquinoline (THIQ) based series of CXCR4 antagonists is presented. Using the previously reported crystal structures which reveal two distinct binding sites of CXCR4 defined as the small molecule (IT1t or minor) binding pocket and peptide (CVX15 or major) binding pocket, we hypothesized our THIQ small molecule series could bind like either molecule in these respective receptor configurations (IT1t versus CVX15 based poses). To this end, a thorough investigation was performed through a combination of receptor mutation studies, medicinal chemistry, biological testing, conformational analysis, and flexible docking. Our findings showed that the CVX15 peptide-based CXCR4 receptor complexes (red pose) were consistently favored over the small molecule IT1t based CXCR4 receptor configurations (blue pose) to correctly explain the computational and mutational studies as well as key structural components of activity for these small molecules.
本文介绍了基于四氢异喹啉（THIQ）系列CXCR4拮抗剂的结构和作用机制原理。利用先前报道的晶体结构，该结构揭示了CXCR4的两个不同结合位点，分别定义为小分子（IT1t或次要）结合口袋和肽（CVX15或主要）结合口袋，我们推测我们的THIQ小分子系列可以像这些各自受体构型中的任何一种分子一样结合（基于IT1t与基于CVX15的构象）。为此，通过受体突变研究、药物化学、生物学测试、构象分析和柔性对接相结合的方式进行了全面研究。我们的研究结果表明，基于CVX15肽的CXCR4受体复合物（红色构象）始终比基于小分子IT1t的CXCR4受体构型（蓝色构象）更受青睐，从而能够正确解释这些小分子的计算和突变研究以及活性的关键结构成分。
