title: IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors.
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 IC50measurements, 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 (IC50= 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.
authors.affiliation: Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS , 1 rue Laurent Fries 67404 CEDEX Illkirch, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.affiliation: Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS , 1 rue Laurent Fries 67404 CEDEX Illkirch, France.|Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona , E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Ruiz
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jindřich
authors.initials: J
authors.lastname: Fanfrlík
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona , E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Giménez-Dejoz
authors.affiliation: Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS , 1 rue Laurent Fries 67404 CEDEX Illkirch, France.
authors.forename: André
authors.initials: A
authors.lastname: Mitschler
authors.affiliation: Department of Organic Chemistry, Charles University in Prague , Hlavova 2030, 128 43 Prague 2, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Kamlar
authors.affiliation: Department of Organic Chemistry, Charles University in Prague , Hlavova 2030, 128 43 Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Veselý
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.|Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Palacký University, Olomouc , 771 46 Olomouc, Czech Republic.
authors.forename: Haresh
authors.initials: H
authors.lastname: Ajani
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona , E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Parés
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona , E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Farrés
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.|Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Palacký University, Olomouc , 771 46 Olomouc, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
authors.affiliation: Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS , 1 rue Laurent Fries 67404 CEDEX Illkirch, France.
authors.forename: Alberto D
authors.initials: AD
authors.lastname: Podjarny
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000074408:Aldo-Keto Reductases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006219:Halogens / Q000737:chemistry*; D015335:Molecular Probes / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D006219:Halogens; D015335:Molecular Probes; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase