IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening.
CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitut...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3340893?pdf=render |
| _version_ | 1818441538511831040 |
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| author | Naomi Tidten-Luksch Raffaella Grimaldi Leah S Torrie Julie A Frearson William N Hunter Ruth Brenk |
| author_facet | Naomi Tidten-Luksch Raffaella Grimaldi Leah S Torrie Julie A Frearson William N Hunter Ruth Brenk |
| author_sort | Naomi Tidten-Luksch |
| collection | DOAJ |
| description | CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens. |
| first_indexed | 2024-12-14T18:29:51Z |
| format | Article |
| id | doaj.art-14264151614b4874805851abdf583349 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T18:29:51Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-14264151614b4874805851abdf5833492022-12-21T22:51:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3579210.1371/journal.pone.0035792IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening.Naomi Tidten-LukschRaffaella GrimaldiLeah S TorrieJulie A FrearsonWilliam N HunterRuth BrenkCDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens.http://europepmc.org/articles/PMC3340893?pdf=render |
| spellingShingle | Naomi Tidten-Luksch Raffaella Grimaldi Leah S Torrie Julie A Frearson William N Hunter Ruth Brenk IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. PLoS ONE |
| title | IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. |
| title_full | IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. |
| title_fullStr | IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. |
| title_full_unstemmed | IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. |
| title_short | IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening. |
| title_sort | ispe inhibitors identified by a combination of in silico and in vitro high throughput screening |
| url | http://europepmc.org/articles/PMC3340893?pdf=render |
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