Title | Structure-based discovery of CFTR potentiators and inhibitors. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Liu F, Kaplan ALevit, Levring J, Einsiedel J, Tiedt S, Distler K, Omattage NS, Kondratov IS, Moroz YS, Pietz HL, Irwin JJ, Gmeiner P, Shoichet BK, Chen J |
Journal | bioRxiv |
Date Published | 2023 Sep 12 |
Abstract | The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while 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 novel 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 novel 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. |
DOI | 10.1101/2023.09.09.557002 |
Alternate Journal | bioRxiv |
PubMed ID | 37745391 |
PubMed Central ID | PMC10515777 |
Grant List | R01 GM133836 / GM / NIGMS NIH HHS / United States R35 GM122481 / GM / NIGMS NIH HHS / United States |
Submitted by bel2021 on February 16, 2024 - 10:39am