6IJX

Crystal Structure of AKR1C1 complexed with meclofenamic acid

6IJX の概要

• エントリーDOI: 10.2210/pdb6ijx/pdb
• 関連するPDBエントリー: 6A7A 6A7B
• 分子名称: Aldo-keto reductase family 1 member C1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[(2,6-dichloro-3-methyl-phenyl)amino]benzoic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, oxidoreductase
• 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: 37878.89

構造登録者

Zheng, X.,Zhao, Y.,Zhang, L.,Zhang, H.,Chen, Y.,Hu, X. (登録日: 2018-10-12, 公開日: 2019-10-16, 最終更新日: 2023-11-22)

主引用文献

Zheng, X.,Jiang, Z.,Li, X.,Zhang, C.,Li, Z.,Wu, Y.,Wang, X.,Zhang, C.,Luo, H.B.,Xu, J.,Wu, D.
Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors.
Bioorg.Med.Chem., 26:5934-5943, 2018

PubMed Abstract: AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.

PubMed: 30429100
DOI: 10.1016/j.bmc.2018.10.044

実験手法

X-RAY DIFFRACTION (2.2 Å)