MP6 Quantitative Structure Activity Relationships (QSARs)
Monday, 14 November 2005: 8:00 AM - 5:30 PM in Exhibit Hall

(TOD-1117-800366) A QSAR Evaluation of AR Binding Affinity of Chemicals.

Mekenyan, O¹, Todorov, M, Serafimova, R ¹, Schmieder, P², Aladjov, H², ¹ Laboratory of Mathematical Chemistry, Bourgas As. Zlatarov University, Bourgas, Bulgaria² U.S. Environmental Protection Agency, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN, USA

ABSTRACT- Some of the environmental and industrial chemicals can interact with the androgen receptor (AR) by mimicking the functions of natural hormones. The multiparameter formulation of COmmon REactivity PAttern (COREPA) approach was used to describe the structural requirements for eliciting androgen potency. Structurally diverse training data set containing 202 chemicals was obtained from the National Center for Toxicology Research (NCTR, US). In agreement with previous models, chemical affinities for the ratAR were related to distances between nucleophilic sites and structural features describing electronic interactions between the receptor and ligands. A single binding mechanism was identified similar to the steroidal A-B electronic mechanism identified for ER binding activity. The COREPA model predicting AR binders with relative binding affinity (RBA) higher then 10% (all steroids) contains: a distance screen of 10.55-10.90 A between hydroxyl O and sp2-hybridized O-atom combined with a classification node containing 2 discriminated parameters - maximal donor delocalizability and LogKow. Almost same decision tree was obtained for the AR activity range 0.1

Key words: androgens, receptor interactions, QSAR