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PREDICTING RETINOID RECEPTOR BINDING AFFINITY: COREPA-M APPLICATION
Citation:
Nedyalkoval, Z., G T. Ankley, AND O. G. Mekenyan. PREDICTING RETINOID RECEPTOR BINDING AFFINITY: COREPA-M APPLICATION. Presented at 10th International Workshop on Structure Activity Relationships (QSARs), Ottawa, Ontario, Canada, May 25-29, 2002.
Description:
Retinoic acid and associated vitamin A derivatives comprise a class of endogenous hormones that activate different retinoic acid receptors RARs). Transcriptional events subsequent to this activation are key to controlling several aspects of vertebrate development. As such, identification of potential RAR agonists is of interest both from a pharmaceutical and toxicological perspective. In a previous study, we used the COREPA approach to describe the activation profile of different retinoid receptor by 17 structurally-diverse retinoids. It has been shown that reactivity patterns for three different subclasses of the RAR receptor (?,?,?) were similar in terms of their global electrophilicity (nucleophilicity) and steric parameters. However, the profile of active chemicals with respect to interaction with the RXR-? differed significantly from that of the RARs, likely reflecting functional differences in the receptors. Conformational analysis of the studied retinoids, in terms of thermodynamic stability of conformers and rotational barriers for their interconversion showed that these chemicals tend to be quite flexible. This established flexibility, and the observation that relatively small energy differences between conformers can result in significant variations in electronic structure highlighted the necessity of considering all energetically-reasonable conformers in defining common reactivity profiles. In the present study, we expand that analysis through the application of the present formulation of the COREPA method to modeling the relative binding affinity of 140 synthetic retinoids to the RAR-?, RAR-? And RAR-?. In difference with the original version of COREPA, where the probabilistic distributions are estimated across single steoelectronic parameters, in the augmented method (COREPA-M) the reactivity pattern is determined in a multi-dimensional space, which enhances discriminatory capability of the method. This abstract does not necessarily reflect USEPA policy.