To find out potential GDNF family receptor α1 (GFRα1) 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 GFRα1 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 GFRα1-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.
Pubmed ID: 30023796 RIS Download
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Software suite of automated docking tools. Designed to predict how small molecules, such as substrates or drug candidates, bind to receptor of known 3D structure. AutoDock consist of AutoDock 4 and AutoDock Vina. AutoDock 4 consists of autodock to perform docking of ligand to set of grids describing target protein, and autogrid to pre calculate these grids.
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