scaffold-based pan-agonist design for the pparα, pparβ and pparγ receptorsscaffold-based pan-agonist设计pparα,pparβpparγ受体.pdfVIP

Scaffold-Based Pan-Agonist Design for the PPARa, PPARb and PPARc Receptors 1. 1. 2 1 3,4 Li-Song Zhang , Shu-Qing Wang , Wei-Ren Xu , Run-Ling Wang *, Jing-Fang Wang * 1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China, 2 Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, China, 3 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China, 4 Shanghai Center for Bioinformation Technology, Shanghai, China Abstract As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR) play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARa, PPARb and PPARc, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARa/c and PPARb/c dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARa, PPARb and PPARc. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 com