Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine.
Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, 40402, Taiwan.
Kuan-Chung
KC
Chen
Su-Sen
SS
Chang
Hung-Jin
HJ
Huang
Tu-Liang
TL
Lin
Yong-Jiang
YJ
Wu
Calvin Yu-Chian
CY
Chen
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry*; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000819:agonists / Q000737:chemistry*; D047494:PPAR delta / Q000819:agonists / Q000737:chemistry*; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry*; D054852:Small Molecule Libraries; D040681:Structural Homology, Protein
D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D054852:Small Molecule Libraries