7P4E
Crystal structure of PPARgamma in complex with compound FL217
Summary for 7P4E
| Entry DOI | 10.2210/pdb7p4e/pdb |
| Descriptor | 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) |
| Functional Keywords | complex, structural genomics, structural genomics consortium, sgc, dna binding protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32681.81 |
| Authors | Ni, X.,Lillich, F.,Proschak, E.,Chaikuad, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2021-07-11, release date: 2022-07-06, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 34818007DOI: 10.1021/acs.jmedchem.1c01331 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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