6I47

Structure of P. aeruginosa LpxC with compound 10: (2RS)-4-(5-(2-Fluoro-4-methoxyphenyl)-1-oxoisoindolin-2-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

これはPDB形式変換不可エントリーです。

6I47 の概要

• エントリーDOI: 10.2210/pdb6i47/pdb
• 分子名称: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, (2~{R})-4-[6-(2-fluoranyl-4-methoxy-phenyl)-3-oxidanylidene-1~{H}-isoindol-2-yl]-2-methyl-2-methylsulfonyl-~{N}-oxidanyl-butanamide, ... (5 entities in total)
• 機能のキーワード: inhibitor, hydrolase
• 由来する生物種: Pseudomonas aeruginosa (strain LESB58)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34112.99

構造登録者

Surivet, J.-P.,Panchaud, P.,Specklin, J.-L.,Diethelm, S.,Blumstein, A.-C.,Gauvin, J.-C.,Jacob, L.,Masse, F.,Mathieu, G.,Mirre, A.,Schmitt, C.,Enderlin-Paput, M.,Lange, R.,Bur, D.,Tidten-Luksch, N.,Gnerre, C.,Seeland, S.,Hermann, C.,Locher, H.H.,Seiler, P.,Mac Sweeney, A.,Hubschwerlen, C.,Ritz, D.,Rueedi, G. (登録日: 2018-11-09, 公開日: 2019-12-18, 最終更新日: 2024-01-24)

主引用文献

Surivet, J.P.,Panchaud, P.,Specklin, J.L.,Diethelm, S.,Blumstein, A.C.,Gauvin, J.C.,Jacob, L.,Masse, F.,Mathieu, G.,Mirre, A.,Schmitt, C.,Lange, R.,Tidten-Luksch, N.,Gnerre, C.,Seeland, S.,Herrmann, C.,Seiler, P.,Enderlin-Paput, M.,Mac Sweeney, A.,Wicki, M.,Hubschwerlen, C.,Ritz, D.,Rueedi, G.
Discovery of Novel Inhibitors of LpxC Displaying Potent in Vitro Activity against Gram-Negative Bacteria.
J.Med.Chem., 63:66-87, 2020

PubMed Abstract: UDP-3--(()-3-hydroxymyristoyl)--glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6-thieno[2,3-]pyrrol-6-ones, and (iii) 1,2-dihydro-3-pyrrolo[1,2-]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as , are discussed.

PubMed: 31804826
DOI: 10.1021/acs.jmedchem.9b01604

実験手法

X-RAY DIFFRACTION (1.9 Å)