Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

Ori Kalid, Martin Mense, Sharon Fischman, Alina Shitrit, Hermann Bihler, Efrat Ben-Zeev, Nili Schutz, Nicoletta Pedemonte, Philip J. Thomas, Robert J. Bridges, Diana R. Wetmore, Yael Marantz, Hanoch Senderowitz

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD 1:2:ICL 1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, ∼tenfold higher than hit rates obtained in corresponding highthroughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

Original languageEnglish
Pages (from-to)971-991
Number of pages21
JournalJournal of Computer-Aided Molecular Design
Issue number12
StatePublished - Dec 2010

Bibliographical note

Funding Information:
Acknowledgments This work was funded by Cystic Fibrosis Foundation Therapeutics. The authors would like to thank Luis Galietta and ChanTest, Inc. for their contribution to the in vitro screening presented in this paper. Special thanks to Melissa Ashlock, Julie Forman-Kay, David Gadsby, and Kevin Foskett for insightful discussions and advice. Excellent technical assistance was provided by Jan Harrington, Linda Coulson, Katelyn Cassidy and Linda Millen.


  • CFTR
  • Chemical chaperones
  • Correctors
  • Cystic fibrosis
  • Docking
  • F508
  • Homology modeling
  • Modulators
  • Pharmacological chaperones
  • Potentiators
  • Structure-based virtual screening
  • Ussing chamber
  • YFP


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