Structure-based discovery of CFTR potentiators and inhibitors

Cell. 2024 Jul 11;187(14):3712-3725.e34. doi: 10.1016/j.cell.2024.04.046. Epub 2024 May 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.

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

MeSH terms

  • Allosteric Site / drug effects
  • Aminophenols* / chemistry
  • Aminophenols* / pharmacology
  • Aminophenols* / therapeutic use
  • Animals
  • Cryoelectron Microscopy
  • Cystic Fibrosis Transmembrane Conductance Regulator* / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / metabolism
  • Drug Discovery
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Quinolones / chemistry
  • Quinolones / pharmacology
  • Quinolones / therapeutic use

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • Aminophenols
  • Quinolones
  • CFTR protein, human
  • Ligands