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Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB)
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Sova, Matej, Cadez, Gasper, Turk, Samo, Majce, Vita, Polanc, Slovenko, Batson, Sarah, Lloyd, Adrian, Roper, David I., Fishwick, Colin W. G. and Gobec, Stanislav (2009) Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB). Bioorganic & Medicinal Chemistry Letters, Vol.19 (No.5). pp. 1376-1379. doi:10.1016/j.bmcl.2009.01.034
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Official URL: http://dx.doi.org/10.1016/j.bmcl.2009.01.034
Abstract
The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in Staphylococcus aureus and Enteroccoccus species. The de novo molecular design programme SPROUT was used in conjunction with the X-ray crystal structure of Enterococcus faecium D-alanyl-D-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on D-Ala-D-Ala ligase (DdlB) from Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB. (C) 2009 Elsevier Ltd. All rights reserved.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) | ||||
| Journal or Publication Title: | Bioorganic & Medicinal Chemistry Letters | ||||
| Publisher: | Pergamon-Elsevier Science Ltd. | ||||
| ISSN: | 0960-894X | ||||
| Official Date: | 1 March 2009 | ||||
| Dates: |
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| Volume: | Vol.19 | ||||
| Number: | No.5 | ||||
| Number of Pages: | 4 | ||||
| Page Range: | pp. 1376-1379 | ||||
| DOI: | 10.1016/j.bmcl.2009.01.034 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | European Union FP6 Integrated Project EUR-INTAFAR, Ministry of Higher Education, Science and Technology of the Republic of Slovenia | ||||
| Grant number: | LSHM-CT-2004-512138 |
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