title: A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor.
abstract: We examined the three-dimensional quantitative structure-activity relationship (QSAR) of a group of endogenous and synthetic compounds for the androgen receptor (AR) using comparative molecular field analysis (CoMFA). The goal of these studies was to identify structural features necessary for high binding affinity and optimization of selective androgen receptor modulators (SARMs). A homology model of the AR was used as a scaffold to align six lead compounds that served as templates for alignment of the remaining 116 structures prior to CoMFA modeling. The conventional r(2) and cross-validated q(2) relating observed and predicted relative binding affinity (RBA) were 0.949 and 0.593, respectively. Comparison of predicted and observed RBA for a test set of 10 compounds resulted in an r(2) of 0.954, demonstrating the excellent predictive ability of the model. These integrated homology modeling and CoMFA studies identified critical amino acids for SARM interactions and provided QSAR data as the basis for mechanistic studies of AR structure, function, and design of optimized SARMs.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Casey E
authors.initials: CE
authors.lastname: Bohl
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mohler
authors.forename: Jiyun
authors.initials: J
authors.lastname: Chen
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Peter W
authors.initials: PW
authors.lastname: Swaan
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000813:Anilides / Q000737:chemistry*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009570:Nitriles; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry*; D011944:Receptors, Androgen / Q000737:chemistry*; D055672:Static Electricity; D013256:Steroids / Q000737:chemistry*; D014105:Tosyl Compounds
chemical_list: D000813:Anilides; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D009570:Nitriles; D011804:Quinolines; D011944:Receptors, Androgen; D013256:Steroids; D014105:Tosyl Compounds; C053541:bicalutamide