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Unveiling the binding mode of adenosine deaminase inhibitors to the active site of the enzyme: implication for rational drug design

2013; Springer Science+Business Media; Volume: 9; Issue: 1 Linguagem: Inglês

10.1007/s11302-013-9353-8

1573-9546

Maria Letizia Trincavelli,

Peptidase Inhibition and Analysis

Limongelli and colleagues describe a novel class of potent adenosine deaminase (ADA) inhibitors, developed as drug candidate for the treatment of inflammatory disorders [1].Since a close correlation has been found between the severity of inflammation and a local increase in both expression and activity of ADA [2], the pharmacological inhibition of this enzyme has recently being regarded as a novel therapeutic approach to counteract inflammation in several pathological conditions.Actually, blockade of the irreversible deamination of adenosine to inosine, normally catalyzed by the enzyme, leads to an increased availability of the biologically active purine at the site of inflammation.Adenosine, in turn, may modulate purinergic responses to these pathological events.Pursuing their interest in this research field [3][4][5][6], and exploiting their synthetic expertise in the synthesis of heterocyclic compounds, authors propose a number of pirazolo[1,5-a]pyrimidin-7-one derivatives bearing suitable alkyl and arylalkyl substituents in the position 4 of the heterocyclic core, which have been shown to inhibit ADA with K i values in the nanomolar range.Although successful in providing novel ADA inhibitors, authors recognize the difficulty of unveiling their mechanism of binding to the