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REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS
Citation:
Ankley, G T., V. Kamenska, S P. Bradbury, AND O. G. Mekenyan. REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS. Presented at Quantitative Structure-Activity Relationship 2000 Meeting, Bourgas, Bulgaria, September 16-20, 2000.
Description:
Retinoids and associated derivatives represent a class of endogenousr hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of normal vertebrate development. Identification of potential RAR and RXRs ligands is of interest both from a pharmaceutical and toxicological perspective. The recently developed COREPA method was used to establish reactivity profiles for a limited data set of retinoid receptor ligands in terms of activation of RAR and RXR. Conformational analysis of a training set of retinoids and related analogues, in terms of thermodynamic stability of conformers and rotational barriers showed that these chemicals tend to be quite flexible. This established flexibility, and the observation that relatively small energy didfferences between conformers can result in significant variations in electronic structure highlighted the necessity of considering all energetically-reasonable conformers in defining common reactivity profiles. The derived reactivity patterns for three different subclasses of the RAR receptor in terms of their global electrophilicity (nucleophilicity) and steric parameters was described. However, the profile of active retinoids with respect to activation of the RXR was found to differ significantly from that of the RARs. Variations in reactivity profiles for the RAR versus RXR families are consistent with established differences in their affinity for endogenous retinoids, likely reflecting functional differences in the receptors.