Ivanova , L , Tammiku-Taul , J , Sidorova , Y , Saarma , M & Karelson , M 2018 , ' Small-Molecule Ligands as Potential GDNF Family Receptor Agonists ' , ACS Omega , vol. 3 , no. 1 , pp. 1022-1030 . https://doi.org/10.1021/acsomega.7b01932
Title: | Small-Molecule Ligands as Potential GDNF Family Receptor Agonists |
Author: | Ivanova, Larisa; Tammiku-Taul, Jaana; Sidorova, Yulia; Saarma, Mart; Karelson, Mati |
Contributor organization: | Institute of Biotechnology Doctoral Programme in Biomedicine Doctoral Programme in Drug Research Doctoral Programme in Integrative Life Science Doctoral Programme Brain & Mind Mart Saarma / Principal Investigator |
Date: | 2018-01 |
Language: | eng |
Number of pages: | 9 |
Belongs to series: | ACS Omega |
ISSN: | 2470-1343 |
DOI: | https://doi.org/10.1021/acsomega.7b01932 |
URI: | http://hdl.handle.net/10138/288716 |
Abstract: | To find out potential GDNF family receptor alpha 1 (GFR alpha 1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRa1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity >= 80%). Five compounds from the ZINC library were tested in phosphorylation and luciferase assays to study their ability to activate GFR alpha 1-RET. A bidental compound with two carboxyl groups showed the highest activity in molecular modeling and biological studies. However, the relative position of these groups was important. The meta-substituted structure otherwise identical to the most active compound 2-[4-(5-carboxy-1H-1,3-benzodiazol-2-yl) phenyl]-1H-1,3-benzodiazole-5-carboxylic acid was inactive. A weaker activity was detected for a compound with a single carboxyl group, that is, 4-(1,3-benzoxazol-2-yl) benzoic acid. The substitution of the carboxyl group by the amino or acetamido group also led to the loss of the activity. |
Subject: |
PARKINSONS-DISEASE
DRUG DESIGN BINDING GFR-ALPHA-1 ACTIVATION NEUROPATHY COMPLEXES INSIGHTS PROTEIN 1182 Biochemistry, cell and molecular biology |
Peer reviewed: | Yes |
Rights: | cc_by |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
Total number of downloads: Loading...
Files | Size | Format | View |
---|---|---|---|
acsomega.7b01932.pdf | 3.538Mb |
View/ |