RESUMO
The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-ß-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 from Serratia marcescens and its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50 > 5 mM).
Assuntos
Compostos de Benzil/farmacologia , Ácido Cítrico/farmacologia , Ésteres/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Compostos de Benzil/química , Ácido Cítrico/química , Relação Dose-Resposta a Droga , Ésteres/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
The cationic ZnII part of aqua-(1,4,7,10-tetra-aza-cyclo-dodeca-ne)zinc(II) bis-(perchlorate), [Zn(C8H20N4)(H2O)](ClO4)2, exhibits a slightly distorted square-pyramidal coordination environment with a water mol-ecule in the apical position. In the crystal, the macrocyclic ring alternates between two conformations with equal occupancies. Two of the three perchlorate anions are situated about a twofold rotation axis, and one of them shows disorder of the O atoms with occupancies of 0.62â (7) and 0.38â (7). In the crystal, the complexes are connected by inter-molecular hydrogen bonding via the perchlorate anions.