Structural Determinants of the Selectivity of 3-Benzyluracil-1-acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10
| Autor: | Alberto Podjarny, Gerhard Klebe, C. Rechlin, Sergio Porté, Andre Mitschler, Xavier Parés, Alexandra Cousido-Siah, Jesús Ángel de la Fuente, Isidro Crespo, María Jesús Martín, Angel R. de Lera, Marta Domínguez, F.X. Ruiz, Jaume Farrés |
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| Rok vydání: | 2015 |
| Předmět: |
Steric effects
Stereochemistry Aldo-Keto Reductases Acetates Molecular Dynamics Simulation Crystallography X-Ray Biochemistry Acetic acid chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Oxidoreductase Aldehyde Reductase Cell Line Tumor Drug Discovery Structure–activity relationship Moiety Humans General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Uracil Cell Proliferation Pharmacology chemistry.chemical_classification Aldose reductase Binding Sites Organic Chemistry Hydrogen Bonding 3. Good health Protein Structure Tertiary Kinetics Enzyme chemistry Drug Design Molecular Medicine Thermodynamics Protein Binding |
| Zdroj: | ChemMedChem. 10(12) |
| ISSN: | 1860-7187 |
| Popis: | The human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly explored in terms of their roles in diabetes, inflammatory disorders, and cancer. In this study we identified two new lead compounds, 2-(3-(4-chloro-3-nitrobenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0048, 3) and 2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0049, 4), which selectively target these enzymes. Although 3 and 4 share the 3-benzyluracil-1-acetic acid scaffold, they have different substituents in their aryl moieties. Inhibition studies along with thermodynamic and structural characterizations of both enzymes revealed that the chloronitrobenzyl moiety of compound 3 can open the AR specificity pocket but not that of the AKR1B10 cognate. In contrast, the larger atoms at the ortho and/or meta positions of compound 4 prevent the AR specificity pocket from opening due to steric hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket, probably enhanced by the displacement of a disordered water molecule trapped in a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this selectivity also occurs in the cell, which enables the development of a more efficient drug design strategy: compound 3 prevents sorbitol accumulation in human retinal ARPE-19 cells, whereas 4 stops proliferation in human lung cancer NCI-H460 cells. |
| Databáze: | OpenAIRE |
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