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NEW DEVELOPMENTS IN A HAZARD IDENTIFICATION ALGORITHM FOR HORMONE RECEPTOR LIGANDS
Citation:
Bradbury, S P., O. G. Mekenyan, AND G T. Ankley. NEW DEVELOPMENTS IN A HAZARD IDENTIFICATION ALGORITHM FOR HORMONE RECEPTOR LIGANDS. Presented at SOT Annual Meeting, New Orleans, LA, March 14-18, 1999.
Description:
Recently we described the COmmon REactivity PAttern (COREPA) techniques to screen data sets of diverse structures for their ability to serve as ligands for steroid hormone receptors (Environ. Sci. Technol. 31:3702-3711). The approach identifies and quantifies similar global and local stereoelectronic characteristics associated with active ligand through a comparison of energetically-reasonable conformer distributions for selected descriptors. For each stereo-
electronic descriptor selected, discrete conformer distributions from a training set of ligands are evaluated and parameter ranges common for conformers from all the chemicals in the training set identified. The use of discrete partitions of parameter ranges to define common reactivity patterns can, however, influence the outcome of the algorithm. To address this limitation, the method has been extended by approximating continuous conformer distributions as probability distributions. The COREPA-Continuous (COREPA-C) algorithm distributions, rather than a collection of common population ranges determined by examination of discrete partitions of a distribution. To illustrate the algorithm, common reactivity patterns based on interatomic distance and charge on heteroatoms were developed and evaluated using a set of 28 androgen receptor ligands. Using receptor binding affinity as the measure of biological activity, the algorithm successfully discriminated active from non-active ligands. Notable attributes of the COREPA-C algorithm include flexibility in establishing stereoelectric descriptor criteria for identifying active and non-active compounds and the ability to quantify three-dimensional chemical similarity without the need to predetermine a toxicophore or align compounds(s) to a lead ligand.