7P4E

Crystal structure of PPARgamma in complex with compound FL217

7P4E の概要

• エントリーDOI: 10.2210/pdb7p4e/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, ~{N}-[[4-(cyclopropylsulfonylamino)-2-(trifluoromethyl)phenyl]methyl]-1-[(3-fluorophenyl)methyl]indole-5-carboxamide, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: complex, structural genomics, structural genomics consortium, sgc, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32681.81

構造登録者

Ni, X.,Lillich, F.,Proschak, E.,Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2021-07-11, 公開日: 2022-07-06, 最終更新日: 2024-01-31)

主引用文献

Lillich, F.F.,Willems, S.,Ni, X.,Kilu, W.,Borkowsky, C.,Brodsky, M.,Kramer, J.S.,Brunst, S.,Hernandez-Olmos, V.,Heering, J.,Schierle, S.,Kestner, R.I.,Mayser, F.M.,Helmstadter, M.,Gobel, T.,Weizel, L.,Namgaladze, D.,Kaiser, A.,Steinhilber, D.,Pfeilschifter, W.,Kahnt, A.S.,Proschak, A.,Chaikuad, A.,Knapp, S.,Merk, D.,Proschak, E.
Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor gamma Agonists/Soluble Epoxide Hydrolase Inhibitors.
J.Med.Chem., 64:17259-17276, 2021

PubMed Abstract: Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor γ (PPARγ) synergistically counteracted MetS in various models, and dual sEH inhibitors/PPARγ agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARγ leads to fluid retention associated with edema and weight gain, while partial PPARγ agonists do not have these drawbacks. In this study, we designed a dual partial PPARγ agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages.

PubMed: 34818007
DOI: 10.1021/acs.jmedchem.1c01331

実験手法

X-RAY DIFFRACTION (2.4 Å)