Bioorg Med Chem. 2009 Mar 1;17(5):1884-9. Epub 2009 Jan 29.

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

Turk S, Kovac A, Boniface A, Bostock JM, Chopra I, Blanot D, Gobec S.

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Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.

Abstract

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 IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).

PMID:: 19223185; [PubMed - indexed for MEDLINE]

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