Ivanova, LarisaTammiku-Taul, JaanaSidorova, YuliaSaarma, MartKarelson, Mati2019-01-092019-01-092018-01Ivanova, 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.7b01932ORCID: /0000-0001-5543-7160/work/52698686http://hdl.handle.net/10138/288716To 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.9engcc_byinfo:eu-repo/semantics/openAccessPARKINSONS-DISEASEDRUG DESIGNBINDINGGFR-ALPHA-1ACTIVATIONNEUROPATHYCOMPLEXESINSIGHTSPROTEINBiochemistry, cell and molecular biologyArticleopenAccessc27e801d-7729-4769-bbab-0fddfb1df81c85053718658000427933200110