5Z6S
Crystal structure of the PPARgamma-LBD complexed with compound DS-6930
Summary for 5Z6S
| Entry DOI | 10.2210/pdb5z6s/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, Peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, 3-[[6-(3,5-dimethylpyridin-2-yl)oxy-1-methyl-benzimidazol-2-yl]methoxy]benzoic acid, ... (5 entities in total) |
| Functional Keywords | transcription |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 34954.29 |
| Authors | Matsui, Y.,Hanzawa, H. (deposition date: 2018-01-25, release date: 2018-10-17, Last modification date: 2023-11-22) |
| Primary citation | Shinozuka, T.,Tsukada, T.,Fujii, K.,Tokumaru, E.,Shimada, K.,Onishi, Y.,Matsui, Y.,Wakimoto, S.,Kuroha, M.,Ogata, T.,Araki, K.,Ohsumi, J.,Sawamura, R.,Watanabe, N.,Yamamoto, H.,Fujimoto, K.,Tani, Y.,Mori, M.,Tanaka, J. Discovery of DS-6930, a potent selective PPAR gamma modulator. Part II: Lead optimization. Bioorg. Med. Chem., 26:5099-5117, 2018 Cited by PubMed Abstract: Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients. PubMed: 30220602DOI: 10.1016/j.bmc.2018.09.005 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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