Projects

Thyroid Receptor

Endocrine disruption: Estimation of the binding affinity of small molecules towards the Thyroid receptor.

Nuclear hormone receptors comprise a class of intracellular, ligand-regulated transcription factors, which include receptors for thyroid hormones. Thyroid hormones exert profound effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles as well as in the liver, and the central nervous system. In addition, they influence the metabolic rate, cholesterol and triglyceride levels, heart rate and an over-all sense of well-being. Two major subtypes exist for the thyroid hormone receptor — α and β — expressed from two different genes. To quantitatively predict the α/β selectivity of adverse effects triggered by the thyroid receptor system, we developed a total of four in silico models based on the TRα1 and TRβ1 structures, respectively. The alignment was obtained using the Yeti technology (automated, flexible docking with dynamic solvation).

Dual-shell Raptor model for the thyroid β receptor subtype.

Our QSAR study was based on a total of 82 compounds, identical for both receptor subtypes. 66 molecules thereof were assigned to the training set and the remaining 16 used as test. The model for TRα1 converged at a crossvalidated r² of 0.812/0.919 (Quasar/Raptor) and yielded a predictive r² of 0.812/0.814 for the test compounds. The model for TRβ1 converged at a cross-validated r² of 0.823/0.909 and yielded a predictive r² of 0.665/0.796 for the test compounds, respectively.

Consensus scoring at the thyroid α1 receptor subtype. Raptor results (left) vs. Quasar results (right).

Reference: ChemMedChem 2007, 2, 78–87. View abstract