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2007 CompTox Forum

Abstract - Combining Structure- and Ligand-Based Approaches to Model Receptor-Mediated Toxic Effects

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Markus A. Lill
Assistant Professor
Department of Medicinal Chemistry and Molecular Pharmacology
Purdue University
Heine Pharmacy Building, Room 506B
575 Stadium Mall Drive, West Lafayette, IN 47907
Phone: 765-496-9375
E-mail: mlill@pharmacy.purdue.edu

An important mechanism of chemical toxicity is mediated by activating or inhibiting receptor-mediated hormonal responses by environmental chemicals. These responses include xenobiotic effects on thyroid hormone receptor, estrogen receptor, and the androgen receptor. One major issue for ligand binding to nuclear receptors is that the protein, in reality, can adapt its shape and properties upon each individual ligand binding to it (induced protein fit). In this context, I will present our development of new concepts incorporating protein flexibility to identify binding modes for ligands of toxicological interest and to quantify their interaction with the target protein. The computational technology combines structure-based molecular docking and novel, multidimensional, quantitative structure activity relationships. Based on our modeling studies on estrogen and androgen receptors, I will discuss our progress and current limitations.

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