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Small-Molecule Ligands as Potential GDNF Family Receptor Agonists.

ABSTRACT: To find out potential GDNF family receptor ?1 (GFR?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 GFR?1 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?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.

SUBMITTER: Ivanova L

PROVIDER: S-EPMC6045390 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Project description:Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer.To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high-throughput screening system and we screened 48,224 compounds from a 100K library in duplicate.We obtained 62 hits using the cut-off criteria of the mean±three standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptor-expressing cells. Molecule MS437 had a TSHR-stimulating potency with an EC50 of 13×10(-8) M, and molecule MS438 had an EC50 of 5.3×10(-8) M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gs?, G??, G?q, and G?12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gs?, G?q, and G?12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the G?? pathway. The small molecules MS437 and MS438 also showed upregulation of thyroglobulin (Tg), sodium iodine symporter (NIS), and TSHR gene expression.Pharmacokinetic analysis of MS437 and MS438 indicated their pharmacotherapeutic potential, and their intraperitoneal administration to normal female mice resulted in significantly increased serum thyroxine levels, which could be maintained by repeated treatments. These molecules can therefore serve as lead molecules for further development of powerful TSH agonists.

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Small-Molecule Ligands as Potential GDNF Family Receptor Agonists.

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