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

compound 1 [PMID: 28611375]   Click here for help

GtoPdb Ligand ID: 9673

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Compound 1 is reported as a direct inhibitor of the protein-protein interaction between TNFα and both of its receptors (TNFRI and TNFRII) [1]. The compound is orally active, which is in contrast to the TNFα biologics that are already in clinical use e.g. infliximab, adalimumab and etanercept. Compound 1 interacts with TNFα in a two-site binding mode with a high affinity site (nM) and a low affinity site (μM) detected [1]. This mechanism interferes with TNFα homotrimer (bioactive cytokine) formation, and thereby inhibits TNF receptor activation. The physicochemical properties of compound 1 are not optimal (especially wrt solubility), so some medicinal chemistry effort would need to be applied to create a more efficient drug-like molecule.
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 6
Hydrogen bond donors 0
Rotatable bonds 8
Topological polar surface area 69.31
Molecular weight 497.15
XLogP 4.79
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 O=C(N1CCN(CC1)Cc1ccccc1)CN(S(=O)(=O)c1ccccc1)c1cccc(c1C)Cl
Isomeric SMILES O=C(N1CCN(CC1)Cc1ccccc1)CN(S(=O)(=O)c1ccccc1)c1cccc(c1C)Cl
InChI InChI=1S/C26H28ClN3O3S/c1-21-24(27)13-8-14-25(21)30(34(32,33)23-11-6-3-7-12-23)20-26(31)29-17-15-28(16-18-29)19-22-9-4-2-5-10-22/h2-14H,15-20H2,1H3
InChI Key QTYHUADZOPIUME-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/)
Bioactivity Comments
Compound 1 inhibits TNFα-induced apoptosis of L929 cells and TNFα-induced NF-κB activation in vitro, and protects mice from TNFκ-dependent hepatic shock in vivo. Compound 1 inhibits TNFα binding to TNFRI (TNFRSF1A; ubiquitously expressed) and TNFRII (TNFRSF1B; expression restricted to hematopoietic cells) with comparable affinity (IC50 ~30μM) [1].
Selectivity at ligand targets
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
tumour necrosis factor shed form Hs Inhibitor Binding 5.3 – 8.6 pKd - 1
⤷ pKd 8.6 (Kd 2.31x10-9 M) [1]
Description: High affinity binding site identified using gravimetric measurements made by surface acoustic wave (SAW) sensors.
pKd 5.3 (Kd 4.79x10-6 M) [1]
Description: Low affinity binding site identified using gravimetric measurements made by surface acoustic wave (SAW) sensors.