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IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors

SYSNO ASEP	0469255
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors
Author(s)	Cousido-Siah, A. (FR) Ruiz, F. X. (FR) Fanfrlík, Jindřich (UOCHB-X)_{RID, ORCID} Giménez-Dejoz, J. (ES) Mitschler, A. (FR) Kamlar, M. (CZ) Veselý, J. (CZ) Ajani, Haresh (UOCHB-X)_{ORCID, RID} Parés, X. (ES) Farrés, J. (ES) Hobza, Pavel (UOCHB-X)_{RID, ORCID} Podjarny, A. D. (FR)
Source Title	ACS Chemical Biology. - : American Chemical Society - ISSN 1554-8929 Roč. 11, č. 10 (2016), s. 2693-2705
Number of pages	13 s.
Language	eng - English
Country	US - United States
Keywords	human aldose reductase ; protein-ligand complexes ; drug design
Subject RIV	CF - Physical ; Theoretical Chemistry
R&D Projects	GBP208/12/G016 GA ČR - Czech Science Foundation (CSF)
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000386187700005
EID SCOPUS	84992188326
DOI	10.1021/acschembio.6b00382
Annotation	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 IC50 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 p-p 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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2017

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