Small-Molecule Ligands as Potential GDNF Family Receptor Agonists

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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 .

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
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.
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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