Docking and Scoring: Applications to PPAR-alpha and PPAR-gamma

Peroxisome proliferators form a diverse group of substances, including many environmental chemicals, which induce a massive accumulation of peroxysomes in hepatocytes and strongly induce enzymes of the peroxysomal and microsomal fatty-acid oxidation systems. Peroxisome proliferators-activated receptors (PPARs) belong to a family of nuclear hormone receptors which, depending on the bound ligand, can directly regulate gene transcription via interaction with response elements. Our goals are to study the binding of environmental chemicals, primarily industrial plasticizers such as phthalates, to PPARs, and to identify further possible binders.

While the work has important public health implications (phthalates are major environmental contaminants in water, food, and soil), it also addresses interesting algorithmic/computational problems. PPAR's have a large binding site, and the different classes of ligands (i.e., full agonists versus partial agonists and antagonists) bind at different regions. Since binding induces conformational changes that directly affect receptor activation and gene expression patterns, it is important to be able to accurately identify the binding modes of potential proliferators. This work is in collaboration with Profs. David Waxman (BU Department of Biology) and Scott Mohr (BU Department of Chemistry).