2. Academic Validation
  3. Structure-based discovery of CFTR potentiators and inhibitors

Structure-based discovery of CFTR potentiators and inhibitors

  • Cell. 2024 May 23:S0092-8674(24)00472-0. doi: 10.1016/j.cell.2024.04.046.
Fangyu Liu 1,  Anat Levit Kaplan 2,  Jesper Levring 3,  Jürgen Einsiedel 4,  Stephanie Tiedt 4,  Katharina Distler 4,  Natalie S Omattage 3,  Ivan S Kondratov 5,  Yurii S Moroz 6,  Harlan L Pietz 3,  John J Irwin 2,  Peter Gmeiner 7,  Brian K Shoichet 8,  Jue Chen 9
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3 Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA.
  • 4 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, D-91058 Erlangen, Germany.
  • 5 Enamine Ltd., Chervonotkatska Street 78, 02094 Kyïv, Ukraine; V.P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyïv, Ukraine.
  • 6 Chemspace, Chervonotkatska Street 85, 02094 Kyïv, Ukraine; Taras Shevchenko National University of Kyïv, Volodymyrska Street 60, 01601 Kyïv, Ukraine.
  • 7 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, D-91058 Erlangen, Germany. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
  • 9 Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: [email protected].
PMID: 38810646 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.

Keywords

ABC transporter; anion channel; inhibitors; large-scale docking; ligand discovery; potentiators.

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