You are here:
The chemistry side of AOP: implications for toxicity extrapolation
Citation:
Barron, M. AND S. Lee. The chemistry side of AOP: implications for toxicity extrapolation. SETAC North America 37th Annual Meeting, Orlando, FL, November 06 - 10, 2016.
Impact/Purpose:
Abstract reporting on chlorinated pesticide contamination in the central Asian Republic of Tajikistan
Description:
An adverse outcome pathway (AOP) is a structured representation of the biological events that lead to adverse impacts following a molecular initiating event caused by chemical interaction with a macromolecule. AOPs have been proposed to facilitate toxicity extrapolation across species through understanding of species similarity in the sequence of molecular, cellular, organ and organismal level responses. However, AOPs are non-specific regarding the identity of the chemical initiators, and the range of structures for which an AOP is considered applicable has generally been poorly defined. Applicability domain has been widely understood in the field of QSAR as the response and chemical structure space in which the model makes predictions with a given reliability, and has been traditionally applied to define the similarity of query molecules within the training set. Three dimensional (3D) receptor modeling offers an approach to better define the applicability domain for selected AOPs through determination of the chemical space of the molecular initiating event. Universal 3D-QSAR models were developed for acetylcholinesterase inhibitors and estrogen receptor agonists and antagonists using a combination of fingerprint, molecular docking and structure-based pharmacophore approaches. The models were based on the critical molecular interactions within each receptor ligand binding domain, and included the key amino acid residues responsible for high binding affinity. The approach allows for extrapolating species sensitivity based on taxa-specific differences in these key amino acids and estimating toxicity for a broad range of chemical structures. Continuing improvements in conformer generation and molecular docking tools, and increasing availability of x-ray crystal structures of receptor-ligand complexes will allow for more efficient and accurate 3D-QSARs and advancement of AOPs from organizing frameworks to predictive models.