The Binding Mode of Second-Generation Sulfonamide Inhibitors of MurD: Clues for Rational Design of Potent MurD InhibitorsReportar como inadecuado




The Binding Mode of Second-Generation Sulfonamide Inhibitors of MurD: Clues for Rational Design of Potent MurD Inhibitors - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

A series of optimized sulfonamide derivatives was recently reported as novel inhibitors of UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase MurD. These are based on naphthalene-N-sulfonyl-D-glutamic acid and have the D-glutamic acid replaced with rigidified mimetics. Here we have defined the binding site of these novel ligands to MurD using 1H-13C heteronuclear single quantum correlation. The MurD protein was selectively 13C-labeled on the methyl groups of Ile δ1 only, Leu and Val, and was isolated and purified. Crucial Ile, Leu and Val methyl groups in the vicinity of the ligand binding site were identified by comparison of chemical shift perturbation patterns among the ligands with various structural elements and known binding modes. The conformational and dynamic properties of the bound ligands and their binding interactions were examined using the transferred nuclear Overhauser effect and saturation transfer difference. In addition, the binding mode of these novel inhibitors was thoroughly examined using unrestrained molecular dynamics simulations. Our results reveal the complex dynamic behavior of ligand–MurD complexes and its influence on ligand–enzyme contacts. We further present important findings for the rational design of potent Mur ligase inhibitors.



Autor: Mihael Simčič, Izidor Sosič, Milan Hodošček, Hélène Barreteau, Didier Blanot, Stanislav Gobec, Simona Golič Grdadolnik

Fuente: http://plos.srce.hr/



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