Three-dimensional (3D) quantitative structure-activity relationship (QSAR) and structure-activity relationship (SAR) analyses were applied concurrently to a data set of highly selective estrogen receptor β (ERβ) agonists. The data set consisted of diphenolic azoles characterized by similar structural skeletons but with different binding modes to the estrogen receptor site. Models were developed separately with respect to the relative binding affinities (RBAs) to ERα and ERβ. Steric and electrostatic fields were calculated for a training set of 72 compounds using comparative molecular field analysis (CoMFA). The model developed for ERα RBA yielded R2 of 0.91 and qcv 2 of 0.60. The model developed for ERβ RBA yielded R2 of 0.95 and qcv 2 of 0.40. Both models were validated successfully using an external test set of 32 compounds. A new concept of test set evaluation based on the variability of the biological response due to the variability of the living organism has been introduced. The CoMFA analysis was supported by a SAR study. In addition to the most favorable steric and electrostatic regions identified by CoMFA, a number of structural descriptors were identified as being important for binding. These are the number of substituents attached to the main skeleton of each compound, the largest distance between the oxygen atoms of each molecule, and the angle defined by the planes that split the phenyl or the naphthyl and the benzisoxazole or the benzoxazole moiety in a morphometrically longitudinal way.
ASJC Scopus subject areas
- Organic Chemistry