GtoPdb is requesting financial support from commercial users. Please see our sustainability page for more information.

CFTRinh-172   Click here for help

GtoPdb Ligand ID: 4153

Compound class: Synthetic organic
Comment: CFTRinh-172 binds within the permeation pathway. However, inhibition is not voltage dependent [3] and results from a collapse of the extracellular mouth of the pore (involving rearrangements of TM8, TM12 and TM1) which occurs after inhibitor binding [2-3,6]. Low apparent potency for the pig CFTR (pIC50 5.7) can be increased by introducting mutations in TM8 (introducing the corresponding human residues), despite TM8 not being part of the CFTRinh-172 binding site [2]. CFTRinh-172 has low water solubility, but more soluble analogues have been developed [5]. It has off-target effects on ClC-2 [1], and volume-sensitive outwardly rectifying Cl− conductance (VSORC) [4].
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 4
Hydrogen bond donors 1
Rotatable bonds 4
Topological polar surface area 115
Molecular weight 409.01
XLogP 3.97
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

✖
Canonical SMILES S=C1SC(=Cc2ccc(cc2)C(=O)O)C(=O)N1c1cccc(c1)C(F)(F)F
Isomeric SMILES S=C1SC(=Cc2ccc(cc2)C(=O)O)C(=O)N1c1cccc(c1)C(F)(F)F
InChI InChI=1S/C18H10F3NO3S2/c19-18(20,21)12-2-1-3-13(9-12)22-15(23)14(27-17(22)26)8-10-4-6-11(7-5-10)16(24)25/h1-9H,(H,24,25)
InChI Key JIMHYXZZCWVCMI-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Cuppoletti J, Chakrabarti J, Tewari KP, Malinowska DH. (2014)
Differentiation between human ClC-2 and CFTR Cl- channels with pharmacological agents.
Am J Physiol Cell Physiol, 307 (5): C479-92. [PMID:25009109]
2. Gao X, Yeh HI, Yang Z, Fan C, Jiang F, Howard RJ, Lindahl E, Kappes JC, Hwang TC. (2024)
Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.
Nat Commun, 15 (1): 6668. [PMID:39107303]
3. Kopeikin Z, Sohma Y, Li M, Hwang TC. (2010)
On the mechanism of CFTR inhibition by a thiazolidinone derivative.
J Gen Physiol, 136 (6): 659-71. [PMID:21078867]
4. Melis N, Tauc M, Cougnon M, Bendahhou S, Giuliano S, Rubera I, Duranton C. (2014)
Revisiting CFTR inhibition: a comparative study of CFTRinh -172 and GlyH-101 inhibitors.
Br J Pharmacol, 171 (15): 3716-27. [PMID:24758416]
5. Sonawane ND, Verkman AS. (2008)
Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis.
Bioorg Med Chem, 16 (17): 8187-95. [PMID:18691893]
6. Young PG, Levring J, Fiedorczuk K, Blanchard SC, Chen J. (2024)
Structural basis for CFTR inhibition by CFTRinh-172.
Proc Natl Acad Sci U S A, 121 (10): e2316675121. [PMID:38422021]