Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.
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 NBD1:2:ICL1:2:4. 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 high-throughput 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.
EPIX Pharmaceuticals Ltd., 3 Hayetzira Street, Ramat Gan, Israel. orikalid@gmail.com
Ori
O
Kalid
Martin
M
Mense
Sharon
S
Fischman
Alina
A
Shitrit
Hermann
H
Bihler
Efrat
E
Ben-Zeev
Nili
N
Schutz
Nicoletta
N
Pedemonte
Philip J
PJ
Thomas
Robert J
RJ
Bridges
Diana R
DR
Wetmore
Yael
Y
Marantz
Hanoch
H
Senderowitz
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D017136:Ion Transport / Q000187:drug effects*; D008958:Models, Molecular; D011485:Protein Binding; D017510:Protein Folding / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000187:drug effects; D017384:Sequence Deletion; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship
D054852:Small Molecule Libraries; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator