6IJX

Crystal Structure of AKR1C1 complexed with meclofenamic acid

Summary for 6IJX

• Entry DOI: 10.2210/pdb6ijx/pdb
• Related: 6A7A 6A7B
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37878.89

Authors

Zheng, X.,Zhao, Y.,Zhang, L.,Zhang, H.,Chen, Y.,Hu, X. (deposition date: 2018-10-12, release date: 2019-10-16, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)