【文章名】Discovery of Novel PPAR Ligands by a Virtual Screening Approach Based on Pharmacophore Modeling, 3D Shape, and Electrostatic Similarity Screening.
[摘要]：Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metab. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested pos. in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compds. 5, 7, and 8 were identified as PPAR-a agonists, whereas compds. 2 and 9 showed agonistic activity for hPPAR-g. Moreover, compd. 9 was identified as a PPAR-d antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidemia, and type 2 diabetes.
