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| | ==Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11== | | ==Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11== |
| - | <StructureSection load='4hld' size='340' side='right' caption='[[4hld]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4hld' size='340' side='right'caption='[[4hld]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hld]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Staar Staar]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HLD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HLD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hld]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MRSA252 Staphylococcus aureus subsp. aureus MRSA252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HLD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HLD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=16T:1-[(3S)-1-{[3-(3-CHLOROPHENOXY)-4-HYDROXYPHENYL]SULFONYL}PIPERIDIN-3-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>16T</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=16T:1-[(3S)-1-{[3-(3-CHLOROPHENOXY)-4-HYDROXYPHENYL]SULFONYL}PIPERIDIN-3-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>16T</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gfd|4gfd]], [[4hdc|4hdc]], [[4gsy|4gsy]], [[4hej|4hej]], [[4hlc|4hlc]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hld OCA], [https://pdbe.org/4hld PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hld RCSB], [https://www.ebi.ac.uk/pdbsum/4hld PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hld ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SAR0483, tmk ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=282458 STAAR])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hld OCA], [http://pdbe.org/4hld PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hld RCSB], [http://www.ebi.ac.uk/pdbsum/4hld PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hld ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KTHY_STAAR KTHY_STAAR]] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity). | + | [https://www.uniprot.org/uniprot/KTHY_STAAR KTHY_STAAR] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Student Project 8 for UMass Chemistry 423 Spring 2015|Student Project 8 for UMass Chemistry 423 Spring 2015]]
| + | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] |
| - | *[[Thymidylate kinase|Thymidylate kinase]] | + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Staar]] | + | [[Category: Large Structures]] |
| - | [[Category: DTMP kinase]] | + | [[Category: Staphylococcus aureus subsp. aureus MRSA252]] |
| - | [[Category: Olivier, N]] | + | [[Category: Olivier N]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Mrsa]]
| + | |
| - | [[Category: Pipiridine]]
| + | |
| - | [[Category: Thymidylate kinase]]
| + | |
| - | [[Category: Tmk]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
KTHY_STAAR Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity).
Publication Abstract from PubMed
Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of logD yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >10(5) selectivity versus the human TMK homologue.
Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).,Martinez-Botella G, Loch JT, Green OM, Kawatkar SP, Olivier NB, Boriack-Sjodin PA, Keating TA Bioorg Med Chem Lett. 2013 Jan 1;23(1):169-73. doi: 10.1016/j.bmcl.2012.10.128., Epub 2012 Nov 5. PMID:23206863[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez-Botella G, Loch JT, Green OM, Kawatkar SP, Olivier NB, Boriack-Sjodin PA, Keating TA. Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK). Bioorg Med Chem Lett. 2013 Jan 1;23(1):169-73. doi: 10.1016/j.bmcl.2012.10.128., Epub 2012 Nov 5. PMID:23206863 doi:http://dx.doi.org/10.1016/j.bmcl.2012.10.128
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