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Cover Picture: Structural Determinants of the Selectivity of 3‐Benzyluracil‐1‐acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10 (ChemMedChem 12/2015)
Author(s) -
Ruiz Francesc X.,
CousidoSiah Alexandra,
Porté Sergio,
Domínguez Marta,
Crespo Isidro,
Rechlin Chris,
Mitschler André,
de Lera Ángel R.,
Martín María Jesús,
de la Fuente Jesús Ángel,
Klebe Gerhard,
Parés Xavier,
Farrés Jaume,
Podjarny Alberto
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Reports
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500528
Subject(s) - aldose reductase , selectivity , acetic acid , chemistry , enzyme , aldo keto reductase , aldehyde reductase , combinatorial chemistry , aldose reductase inhibitor , stereochemistry , reductase , biocatalysis , biochemistry , catalysis , ionic liquid
The front cover picture shows how to achieve selective inhibition of two closely related human enzymes, with different biological activities, using a common scaffold. By switching from a chloro‐3‐nitrobenzyl [in compound 3 , 2‐(3‐(4‐chloro‐3‐nitrobenzyl)‐2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2 H )‐yl)acetic acid] to a tetrabromo‐6‐methoxybenzyl decorated scaffold [in compound 4 , 2‐(2,4‐dioxo‐3‐(2,3,4,5‐tetrabromo‐6‐methoxybenzyl)‐3,4‐dihydropyrimidin‐1(2 H )‐yl)acetic acid], the potency and selectivity profile shifts from aldose reductase (AR) to AKR1B10. The underlying rationale can be grasped from the crystal structures and thermodynamic profiles of AR with 3 and AKR1B10 with 4 , which is graphically depicted by the popular saying “kill two birds with one stone”. This selectivity is also maintained in cellular studies, anticipating an efficient drug design and development towards diabetes, cancer, and inflammation. More details can be found in the Full Paper by Francesc X. Ruiz, Alberto Podjarny et al. on page 1989 in Issue 12, 2015 (DOI: 10.1002/cmdc.201500393).