The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.

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 bind...

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Autores principales:	Mihael Simčič, Izidor Sosič, Milan Hodošček, Hélène Barreteau, Didier Blanot, Stanislav Gobec, Simona Golič Grdadolnik
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/82e2208f27304210bd04393e04fc33af
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spelling	oai:doaj.org-article:82e2208f27304210bd04393e04fc33af2021-11-18T08:04:02ZThe binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.1932-620310.1371/journal.pone.0052817https://doaj.org/article/82e2208f27304210bd04393e04fc33af2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23285193/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203A 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 (1)H/(13)C heteronuclear single quantum correlation. The MurD protein was selectively (13)C-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.Mihael SimčičIzidor SosičMilan HodoščekHélène BarreteauDidier BlanotStanislav GobecSimona Golič GrdadolnikPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e52817 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mihael Simčič Izidor Sosič Milan Hodošček Hélène Barreteau Didier Blanot Stanislav Gobec Simona Golič Grdadolnik The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
description	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 (1)H/(13)C heteronuclear single quantum correlation. The MurD protein was selectively (13)C-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.
format	article
author	Mihael Simčič Izidor Sosič Milan Hodošček Hélène Barreteau Didier Blanot Stanislav Gobec Simona Golič Grdadolnik
author_facet	Mihael Simčič Izidor Sosič Milan Hodošček Hélène Barreteau Didier Blanot Stanislav Gobec Simona Golič Grdadolnik
author_sort	Mihael Simčič
title	The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
title_short	The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
title_full	The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
title_fullStr	The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
title_full_unstemmed	The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.
title_sort	binding mode of second-generation sulfonamide inhibitors of murd: clues for rational design of potent murd inhibitors.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/82e2208f27304210bd04393e04fc33af
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The binding mode of second-generation sulfonamide inhibitors of MurD: clues for rational design of potent MurD inhibitors.

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