Quantitative Structure–activity Relationships for Polychlorinated Hydroxybiphenyl Estrogen Receptor Binding Affinity: An Assessment of Conformer Flexibility

Abstract

A diverse group of xenobiotics has a high binding affinity to the estrogen receptor (ER), suggesting that it can accommodate large variability in ligand structure. Relationships between xenobiotic structure, binding affinity, and estrogenic response have been suggested to be dependent on the conformational structures of the ligands. To explore the influence of conformational flexibility on ER binding affinity, a quantitative structure-activity relationship (QSAR) study was undertaken with estradiol, diethylstilbestrol, and a set of polychlorinated hydroxybiphenyls (PCHBs) of environmental concern. Although the low-energy minima of the PCHB congeners suggested that interconversions among conformers were likely, the electronic parameters associated with the conformer geometries for a specific PCHB congener could vary significantly. The results of the QSAR analysis suggested that among the PCHBs studied, the most polarizable conformers (lower absolute volume polarizability values) were most closely associated with ER binding affinity. Across the set of ''polarizable'' conformers, which did not include the low-energy gas-phase conformers, the electron donating properties of the hydroxy moiety and the aromatic component of the estradiol A ring analogue in the PCHBs were found to be correlated with higher ER binding affinity.

Effect of Substituent Size and Dimensionality on Potency of Phenolic Xenoestrogens Evaluated With a Recombinant Yeast Assay

“…However, comparisons of both slopes and intercepts for the models noted in Equations 1 and 2 revealed limited alteration in values. The unexplained variance in ␤-galactosidase activity may be explained by the conformer flexibility [9,12]. However, a critical examination of this explanation is beyond the scope of these investigations.…”

“…Structure-activity relationships for estrogenicity [7][8][9][10][11][12][13] have, for the most part, used binding data reported by Waller et al [1], Kuiper et al [14], and/or Tabira et al [13]. It is thought that phenols have the potential to produce estrogenic effects by binding directly with the estrogen receptor.…”

The Role of Ligand Flexibility in Predicting Biological Activity: Structure–activity Relationships for Aryl Hydrocarbon, Estrogen, and Androgen Receptor Binding Affinity

“…Following identification of the most planar conformations, structures were further screened to retain only those that were within 20 kcal/mol of the lowest-energy conformation for a given congener. For the studies described in this review [23,36,37], values for the energy minima 0 ⌬H f for both the unoptimized and optimized conformers were typically within 5 to 15 kcal/mol, which is presumed to be within the free energy of binding of ligands to nuclear steroid receptors (e.g., Ϫ12.1 kcal/mol for the binding of E 2 to the ER; see Wiese and Brooks [38]).…”

Quantitative structure‐activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals

“…Quantitative structure-activity relationship models have been developed for several ER-related in vitro endpoints, such as ER binding affinity [14,24,31,35,36,39,40], gene activation [13], and cell proliferation [14,15]. The ER ligand binding affinity serves as an example of a well-defined endpoint for which chemical-biological interaction can be successfully predicted.…”

“…Reactivity patterns were established for identifying and ranking compounds within a series of binding affinity ranges relative to estradiol binding of 100%, including RBA values of Ͼ150%, 100 to 10%, 10 to 1%, and 1 to 0.1%. Local, global, and steric descriptors used in the model were restricted to those hypothesized to be associated with ER binding, based on previous studies with a variety of model receptors [35][36][37][38]45,47,48,[52][53][54][55][56] (see [39] for computational details). Through the COREPA analysis the authors determined that ER RBA could be predicted based on three parameters: global nucleophilicity (represented by energy of the highest occupied molecular orbital, E HOMO ), interatomic distances between nucleophilic heteroatoms, and electron donor capability of these heteroatoms.…”