Structure-based discovery of CFTR potentiators and inhibitors

Liu F, Kaplan AL, Levring J, Einsiedel J, Tiedt S, Distler K, Omattage NS, Kondratov IS, Moroz YS, Pietz HL, Irwin JJ, Gmeiner P, Shoichet BK, Chen J (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 187

Pages Range: 3712-3725.e34

Journal Issue: 14

DOI: 10.1016/j.cell.2024.04.046

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.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Rockefeller University United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Enamine Ltd. Ukraine (UA) Chemspace Ukraine (UA)

How to cite

APA:

Liu, F., Kaplan, A.L., Levring, J., Einsiedel, J., Tiedt, S., Distler, K.,... Chen, J. (2024). Structure-based discovery of CFTR potentiators and inhibitors. Cell, 187(14), 3712-3725.e34. https://doi.org/10.1016/j.cell.2024.04.046

MLA:

Liu, Fangyu, et al. "Structure-based discovery of CFTR potentiators and inhibitors." Cell 187.14 (2024): 3712-3725.e34.

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