美国洛克菲勒大学Jue Chen等研究人员合作报道了CFTR增效剂和抑制剂的基于结构的发现。相关论文于2024年5月28日在线发表在《细胞》杂志上。

研究人员将分子对接、电生理学、冷冻电镜和药物化学结合起来，以确定囊性纤维化跨膜传导调节器（CFTR）调节剂。研究人员将1.55亿个分子对接到CFTR的增效剂位点，合成了53种测试配体，并使用基于结构的优化方法来确定候选调节剂。

这种方法发现了与同一异构位点结合的中纳摩尔增效剂和抑制剂。这些分子是开发治疗囊性纤维化和分泌性腹泻的更有效药物的潜在线索，并证明了大规模对接用于离子通道药物发现的可行性。

据了解，CFTR是一种重要的离子通道，其功能丧失会导致囊性纤维化，而过度激活则会导致分泌性腹泻。目前临床上已有改善CFTR折叠（校正器）或功能（增效剂）的小分子药物。然而，唯一的增效剂ivacaftor的药代动力学不理想，抑制剂也尚未临床开发。

附：英文原文

Title: Structure-based discovery of CFTR potentiators and inhibitors

Author: Fangyu Liu, Anat Levit Kaplan, Jesper Levring, Jürgen Einsiedel, Stephanie Tiedt, Katharina Distler, Natalie S. Omattage, Ivan S. Kondratov, Yurii S. Moroz, Harlan L. Pietz, John J. Irwin, Peter Gmeiner, Brian K. Shoichet, Jue Chen

Issue&Volume: 2024-05-28

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ～155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

DOI: 10.1016/j.cell.2024.04.046

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00472-0