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TitleStructure-based discovery of CFTR potentiators and inhibitors.
Journal, issue, pagesCell, Vol. 187, Issue 14, Page 3712-3725.e34, Year 2024
Publish dateJul 11, 2024
AuthorsFangyu 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 /
PubMed AbstractThe 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 ...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.
External linksCell / PubMed:38810646 / PubMed Central
MethodsEM (single particle)
Resolution3.8 Å
Structure data

40207

8gls

EMDB-40207, PDB-8gls:
Complex of human cystic fibrosis transmembrane conductance regulator (CFTR) and Z1834339853
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM


ChemComp, No image

ChemComp-ZRH:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / transporter / ion channel

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