☆ 4.7 Article

Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening

BIOORGANIC & MEDICINAL CHEMISTRY (2009)

期刊

BIOORGANIC & MEDICINAL CHEMISTRY

卷 17, 期 5, 页码 1884-1889

出版社

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmc.2009.01.052

关键词

Mur ligases; Enzyme inhibitors; Antibacterials; Computational methods

类别

Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic

资金

European Commission through the EUR-INTAFAR project [LSHM-CT-2004-512138]
Centre National de la Recherche Scientifique [UMR 8619, PICS 3729]
Ministry of Higher Education, Science and Technology of the Republic of Slovenia
Franco-Slovene Proteus programme
Institut Charles Nodier (Ljubljana)

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Protocol

Reagent

摘要

The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC50 = 10 mu M) and one novel MurF inhibitor (IC50 = 63 mu M). (C) 2009 Elsevier Ltd. All rights reserved.

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