Androgen receptor binding affinity: a QSAR evaluation

Abstract

The multiparameter formulation of the COmmon REactivity PAttern (COREPA) approach has been used to describe the structural requirements for eliciting rat androgen receptor (AR) binding affinity, accounting for molecular flexibility. Chemical affinity for AR binding was related to the distances between nucleophilic sites and structural features describing electronic and hydrophobic interactions between the receptor and ligands. Categorical models were derived for each binding affinity range in terms of specific distances, local (maximal donor delocalizability associated with the oxygen atom of the A ring), global nucleophilicity (partial positive surface areas and energy of the highest occupied molecular orbital) and hydrophobicity (log Kow) of the molecules. An integral screening tool for predicting binding affinity to AR was constructed as a battery of models, each associated with different activity bins. The quality of the screening battery of models was assessed using a high value (0.9) of the Pearson contingency coefficient. The predictability of the model was assessed by testing the model performance on external validation sets. A recently developed technique for selection of potential androgenically active chemicals was used to test the performance of the model in its applicability domain. Some of the selected chemicals were tested for AR transcriptional activation. The experimental results confirmed the theoretical predictions.

Keywords:

• androgen binding
• hormonal toxicity
• molecular flexibility
• strategic chemical selection
• QSAR