Simulating α/β Selectivity at the Human Thyroid Hormone Receptor: Consensus Scoring Using Multidimensional QSAR

We present a consensus‐scoring study on the human thyroid hormone receptor α and β using two receptor‐modeling concepts (software Quasar and Raptor) that are based on multidimensional QSAR and allow for the explicit simulation of induced fit. The binding mode of 82 agonists and indirect antagonists, spanning an activity range of seven orders of magnitude in Ki, was identified through flexible docking to the respective X‐ray crystal structures (Yeti software) and represented by a 4D data set with up to four conformations per compound. The receptor surrogates for the thyroid α receptor converged at a cross‐validated r2 of 0.846/0.919 (64 training compounds; for Quasar and Raptor, respectively) and yielded a predictive r2 of 0.812/0.814 (18 test compounds); the models for the thyroid β receptor resulted in a cross‐validated r2 of 0.823/0.909 and a predictive r2 of 0.665/0.796, respectively. Consensus was achieved as, on average, the calculated activities of the training set differ only by a factor of 2.2 in Ki and those of the test set by a factor of 2.8 when predicted by Quasar and Raptor, respectively.

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