QSAR and mechanistic interpretation of estrogen receptor binding

A multi-dimensional formulation of the COmmon REactivity PAttern (COREPA) modeling approach has been used to investigate chemical binding to the human estrogen receptor (hER). A training set of 645 chemicals included 497 steroid and environmental chemicals (database of the Chemical Evaluation and Research Institute, Japan - CERI) and 148 chemicals to further explore hER-structure interactions (selected J. Katzenellenbogen references). Upgrades of modeling approaches were introduced for multivariate COREPA analysis, optimal conformational generation and description of the local hydrophobicity of chemicals. Analysis of reactivity patterns based on the distance between nucleophilic sites resulted in identification of distinct interaction types: a steroid-like A–B type described by frontier orbital energies and distance between nucleophilic sites with specific charge requirements; an A–C type where local hydrophobic effects are combined with electronic interactions to modulate binding; and mixed A–B–C (AD) type. Chemicals were grouped by type, then COREPA models were developed for within specific relative binding affinity ranges of >10%, 10 > RBA ≥ 0.1%, and 0.1 > RBA > 0.0%. The derived models for each interaction type and affinity range combined specific prefiltering requirements (interatomic distances) and a COREPA classification node using no more than 2 discriminating parameters. The interaction types are becoming less distinct in the lowest activity range for each chemicals of each type; here, the modeling was performed within chemical classes (phenols, phthalates, etc.). The ultimate model was organized as a battery of local models associated to interaction type and mechanism. §Presented at the 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology (QSAR2006), 8–12 May 2006, Lyon, France.