Structural Determinants of the Selectivity of 3‐Benzyluracil‐1‐acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10 |
| |
| Authors: | Dr. Francesc X. Ruiz Alexandra Cousido‐Siah Dr. Sergio Porté Dr. Marta Domínguez Isidro Crespo Chris Rechlin Dr. André Mitschler Prof. Dr. Ángel R. de Lera Dr. María Jesús Martín Dr. Jesús Ángel de la Fuente Prof. Dr. Gerhard Klebe Prof. Dr. Xavier Parés Prof. Dr. Jaume Farrés Dr. Alberto Podjarny |
| |
| Affiliation: | 1. Department of Integrative Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, UdS, Illkirch CEDEX, France;2. Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, (USA);3. Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain;4. Departmento de Química Orgánica and Centro de Investigaciones Biomédicas (CINBIO), Universidade de Vigo, Vigo, Spain;5. Institute of Pharmaceutical Chemistry, University of Marburg, Marburg, Germany;6. Biomar Microbial Technologies S.A., Parque Tecnológico de León, León, Spain |
| |
| Abstract: | 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. |
| |
| Keywords: | aldose reductase AKR1B10 drug design steric hindrance buried water molecule |
|
|
