title: Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone.
abstract: The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, People's Republic of China.
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Xu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Xian-Chao
authors.initials: XC
authors.lastname: Cheng
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Run-Ling
authors.initials: RL
authors.lastname: Wang
mesh_terms: D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: ADMET; PPARs; diabetes; docking; molecular dynamics simulation