Three-dimensional structure-activity relationships of nonsteroidal ligands in complex with androgen receptor ligand-binding domain.

We studied the three-dimensional quantitative structure-activity relationships (3D QSAR) of 70 structurally and functionally diverse androgen receptor (AR) binding compounds using the comparative molecular similarity indices analysis (CoMSIA) method. The compound set contained 67 nonsteroidal analogues of flutamide, nilutamide, and bicalutamide whose binding mode to AR was unknown. Docking was used to identify the preferred binding modes for the nonsteroidal compounds within the AR ligand-binding pocket (LBP) and to generate the ligand alignment for the 3D QSAR analysis. The alignment produced a statistically significant and predictive model, validated by random group cross-validation and external test sets (q(2)(LOO) = 0.656, SDEP = 0.576, r(2) = 0.911, SEE = 0.293; q(2)(10) = 0.612, q(2)(5) = 0.571; pred-r(2) = 0.800). Additional model validation comes from the CoMSIA maps that were interpreted with respect to the LBP structure. The model takes into account and links the AR LBP structure, docked ligand structures, and the experimental binding activities. The results provide valuable information on intermolecular interactions between nonsteroidal ligands and the AR LBP.