QSAR and mechanistic interpretation of estrogen receptor binding

摘要

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 conforma-tional 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 specificprefiltering 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.