5OUJ

Crystal structure of human AKR1B1 complexed with NADP+ and compound 39

Summary for 5OUJ

• Entry DOI: 10.2210/pdb5ouj/pdb
• Related: 4IGS 5OU0 5OUK
• Descriptor: Aldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[(1~{R})-5-(4-chlorophenyl)-9-fluoranyl-3-methyl-1-oxidanyl-1~{H}-pyrimido[4,5-c]quinolin-2-yl]ethanoic acid, ... (4 entities in total)
• Functional Keywords: alpha-beta tim barrel, cytosol, aldo-keto reductase, pyrimido[4, 5-c]quinolone-2-acetic acid scaffold, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 37041.55

Authors

Cousido-Siah, A.,Ruiz, F.X.,Mitschler, A.,Metwally, K.,Podjarny, A. (deposition date: 2017-08-24, release date: 2018-05-09, Last modification date: 2024-01-17)

Primary citation

Crespo, I.,Gimenez-Dejoz, J.,Porte, S.,Cousido-Siah, A.,Mitschler, A.,Podjarny, A.,Pratsinis, H.,Kletsas, D.,Pares, X.,Ruiz, F.X.,Metwally, K.,Farres, J.
Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase.
Eur J Med Chem, 152:160-174, 2018

PubMed Abstract: Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kvs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.

PubMed: 29705708
DOI: 10.1016/j.ejmech.2018.04.015

Experimental method

X-RAY DIFFRACTION (0.96 Å)