5LIX

Crystal structure of human AKR1B10 complexed with NADP+ and the inhibitor MK184

Summary for 5LIX

• Entry DOI: 10.2210/pdb5lix/pdb
• Descriptor: Aldo-keto reductase family 1 member B10, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, {5-chloro-2-[(2,4,6-tribromobenzyl)carbamoyl]phenoxy}acetic acid, ... (5 entities in total)
• Functional Keywords: alpha-beta tim barrel, cytosol, aldo-keto reductase, halogenated ligand, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome : O60218
• Total number of polymer chains: 1
• Total formula weight: 37768.96

Authors

Cousido-Siah, A.,Ruiz, F.X.,Mitschler, A.,Fanfrlik, J.,Kamlar, M.,Vesely, J.,Hobza, P.,Podjarny, A. (deposition date: 2016-07-15, release date: 2016-07-27, Last modification date: 2024-01-10)

Primary citation

Cousido-Siah, A.,Ruiz, F.X.,Fanfrlik, J.,Gimenez-Dejoz, J.,Mitschler, A.,Kamlar, M.,Vesely, J.,Ajani, H.,Pares, X.,Farres, J.,Hobza, P.,Podjarny, A.D.
IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors.
Acs Chem.Biol., 11:2693-2705, 2016

PubMed Abstract: Human enzyme aldo-keto reductase family member 1B10 (AKR1B10) has evolved as a tumor marker and promising antineoplastic target. It shares high structural similarity with the diabetes target enzyme aldose reductase (AR). Starting from the potent AR inhibitor IDD388, we have synthesized a series of derivatives bearing the same halophenoxyacetic acid moiety with an increasing number of bromine (Br) atoms on its aryl moiety. Next, by means of IC measurements, X-ray crystallography, WaterMap analysis, and advanced binding free energy calculations with a quantum-mechanical (QM) approach, we have studied their structure-activity relationship (SAR) against both enzymes. The introduction of Br substituents decreases AR inhibition potency but improves it in the case of AKR1B10. Indeed, the Br atoms in ortho position may impede these drugs to fit into the AR prototypical specificity pocket. For AKR1B10, the smaller aryl moieties of MK181 and IDD388 can bind into the external loop A subpocket. Instead, the bulkier MK184, MK319, and MK204 open an inner specificity pocket in AKR1B10 characterized by a π-π stacking interaction of their aryl moieties and Trp112 side chain in the native conformation (not possible in AR). Among the three compounds, only MK204 can make a strong halogen bond with the protein (-4.4 kcal/mol, using QM calculations), while presenting the lowest desolvation cost among all the series, translated into the most selective and inhibitory potency AKR1B10 (IC = 80 nM). Overall, SAR of these IDD388 polyhalogenated derivatives have unveiled several distinctive AKR1B10 features (shape, flexibility, hydration) that can be exploited to design novel types of AKR1B10 selective drugs.

PubMed: 27359042
DOI: 10.1021/acschembio.6b00382

Experimental method

X-RAY DIFFRACTION (1.95 Å)