title: Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.
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: PPARα, PPARβ and PPARγ, 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 PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. 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 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especially Cpd#1) hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, China.
authors.forename: Li-Song
authors.initials: LS
authors.lastname: Zhang
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Xu
authors.forename: Run-Ling
authors.initials: RL
authors.lastname: Wang
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Wang
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047493:PPAR alpha / Q000819:agonists / Q000737:chemistry*; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry*; D048068:PPAR-beta / Q000819:agonists / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
chemical_list: D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta