Premium
Simulating α/β Selectivity at the Human Thyroid Hormone Receptor: Consensus Scoring Using Multidimensional QSAR
Author(s) -
Vedani Angelo,
Zumstein Martin,
Lill Markus A.,
Ernst Beat
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600212
Subject(s) - quantitative structure–activity relationship , thyroid hormone receptor , test set , thyroid , hormone , computational biology , hormone receptor , docking (animal) , chemistry , computer science , biology , medicine , stereochemistry , endocrinology , artificial intelligence , cancer , breast cancer , nursing
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 K i , 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 r 2 of 0.846/0.919 (64 training compounds; for Quasar and Raptor, respectively) and yielded a predictive r 2 of 0.812/0.814 (18 test compounds); the models for the thyroid β receptor resulted in a cross‐validated r 2 of 0.823/0.909 and a predictive r 2 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 K i and those of the test set by a factor of 2.8 when predicted by Quasar and Raptor, respectively.