Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell. 2024 Jul 11;187(14):3712-3725.e34. doi: 10.1016/j.cell.2024.04.046. Epub 2024 May 28.
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.
囊性纤维化跨膜电导调节因子（CFTR）是一种重要的离子通道，其功能丧失会导致囊性纤维化，而其过度激活则会导致分泌性腹泻。能够改善 CFTR 折叠（矫正剂）或功能（增强剂）的小分子在临床上已经可用。然而，唯一的增强剂 ivacaftor 的药代动力学并不理想，抑制剂尚未在临床上开发出来。在这里，我们将分子对接、电生理学、冷冻电镜和药物化学结合起来，以鉴定 CFTR 调节剂。我们将大约 1.55 亿个分子对接进入 CFTR 的增强剂结合位点，合成了 53 个测试配体，并使用基于结构的优化来鉴定候选调节剂。这种方法发现了具有中纳摩尔效力的增强剂，以及与相同别构位点结合的抑制剂。这些分子为开发更有效的囊性纤维化和分泌性腹泻药物提供了潜在的先导化合物，证明了大规模对接用于离子通道药物发现的可行性。
