Bookmark and Share
BioAssay: AID 210957

The second dissociation constant for binding to WT TTR determined by isothermal titration calorimetry (25 C, pH 8.0)

Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical more ..
_
   
 Tested Compounds
 Tested Compounds
All(3)
 
 
Active(2)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Active(2)
 
 
Unspecified(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 210957
Data Source: ChEMBL (208272)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-24
Modify Date: 2014-05-21

Data Table ( Complete ):           View Active Data    View All Data
BioActive Compounds: 2
Description:
Title: Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis.

Abstract: Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR.18(2) and TTR.20(2) complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the epsilon-ammonium groups of Lys 15 and 15'. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117' residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR.1(2) structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.
(PMID: 14711308)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Putative Target:

ChEMBL Target ID: 12704
Target Type: SINGLE PROTEIN
Pref Name: Transthyretin
Synonyms: ATTR;Prealbumin;TBPA;Transthyretin;
Gene Name: PALB;TTR;
Protein Accession: P02766;
Protein GI: 136464;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: unclassified
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment
Assay Type: Binding

Assay Data Source: Scientific Literature

BAO: Assay Format: biochemical format

Result Definitions
Show more
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Kd2 activity commentKd2 activity commentString
2Kd2 standard flagKd2 standard flagInteger
3Kd2 qualifierKd2 qualifierString
4Kd2 published valueKd2 published valueFloat
5Kd2 standard valueKd2 standard valueFloat
6Kd2 activity commentKd2 activity commentString
7Kd2 standard flagKd2 standard flagInteger
8Kd2 qualifierKd2 qualifierString
9Kd2 published valueKd2 published valueFloatnM
10Kd2 standard valueKd2 standard valueFloatnM

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
PageFrom: