3O9V

Crystal Structure of Human DPP4 Bound to TAK-986

3O9V の概要

• エントリーDOI: 10.2210/pdb3o9v/pdb
• 関連するPDBエントリー: 3O95
• 分子名称: Dipeptidyl peptidase 4, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridine-3-carboxic acid, ... (5 entities in total)
• 機能のキーワード: protease and 8-bladed beta-propeller domain, aminopeptidase, cell membrane, glycoprotein, hydrolase, membrane, protease, secreted, serine protease, signal-anchor, transmembrane, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 348687.49

構造登録者

Yano, J.K.,Aertgeerts, K. (登録日: 2010-08-04, 公開日: 2011-02-09, 最終更新日: 2024-11-06)

主引用文献

Miyamoto, Y.,Banno, Y.,Yamashita, T.,Fujimoto, T.,Oi, S.,Moritoh, Y.,Asakawa, T.,Kataoka, O.,Yashiro, H.,Takeuchi, K.,Suzuki, N.,Ikedo, K.,Kosaka, T.,Tsubotani, S.,Tani, A.,Sasaki, M.,Funami, M.,Amano, M.,Yamamoto, Y.,Aertgeerts, K.,Yano, J.,Maezaki, H.
Discovery of a 3-Pyridylacetic Acid Derivative (TAK-100) as a Potent, Selective and Orally Active Dipeptidyl Peptidase IV (DPP-4) Inhibitor.
J.Med.Chem., 53:3517-3531, 2011

PubMed Abstract: Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.

PubMed: 21218817
DOI: 10.1021/jm101236h

実験手法

X-RAY DIFFRACTION (2.75 Å)