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==Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16== | ==Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16== | ||
<StructureSection load='4hej' size='340' side='right' caption='[[4hej]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='4hej' size='340' side='right'caption='[[4hej]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4hej]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4hej]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_N315 Staphylococcus aureus subsp. aureus N315]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HEJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=14D:5-METHYL-1-[(3S)-1-{3-[3-(TRIFLUOROMETHYL)PHENOXY]BENZYL}PIPERIDIN-3-YL]PYRIMIDINE-2,4(1H,3H)-DIONE'>14D</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=14D:5-METHYL-1-[(3S)-1-{3-[3-(TRIFLUOROMETHYL)PHENOXY]BENZYL}PIPERIDIN-3-YL]PYRIMIDINE-2,4(1H,3H)-DIONE'>14D</scene></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=4hej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hej OCA], [https://pdbe.org/4hej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hej RCSB], [https://www.ebi.ac.uk/pdbsum/4hej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hej ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/KTHY_STAAN KTHY_STAAN] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis.[HAMAP-Rule:MF_00165] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 20: | ||
==See Also== | ==See Also== | ||
*[[Thymidylate kinase|Thymidylate kinase]] | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Staphylococcus aureus subsp. aureus N315]] | ||
[[Category: Breen | [[Category: Breen J]] | ||
[[Category: Duffy | [[Category: Duffy J]] | ||
[[Category: Dumas | [[Category: Dumas J]] | ||
[[Category: Geng | [[Category: Geng B]] | ||
[[Category: Gowers | [[Category: Gowers I]] | ||
[[Category: Green | [[Category: Green O]] | ||
[[Category: Guler | [[Category: Guler S]] | ||
[[Category: Hentemann | [[Category: Hentemann M]] | ||
[[Category: Hernandez-Juan | [[Category: Hernandez-Juan F]] | ||
[[Category: Joseph-McCarthy | [[Category: Joseph-McCarthy D]] | ||
[[Category: Kawatkar | [[Category: Kawatkar S]] | ||
[[Category: Larsen | [[Category: Larsen N]] | ||
[[Category: Lazari | [[Category: Lazari O]] | ||
[[Category: Loch | [[Category: Loch J]] | ||
[[Category: Macritchie | [[Category: Macritchie J]] | ||
[[Category: Martinez-Botella | [[Category: Martinez-Botella G]] | ||
Revision as of 11:12, 3 November 2022
Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16
Structural highlights
FunctionKTHY_STAAN Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis.[HAMAP-Rule:MF_00165] Publication Abstract from PubMedThymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by x-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs <1 ug/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog. Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK).,Martinez-Botella G, Breen JN, Duffy JE, Dumas J, Geng B, Gowers IK, Green OM, Guler S, Hentemann MF, Hernandez-Juan FA, Joseph-McCarthy D, Kawatkar SP, Larsen NA, Lazari O, Loch JT, Macritchie JA, McKenzie AR, Newman JV, Olivier NB, Otterson LG, Owens AP, Read J, Sheppard DW, Keating TA J Med Chem. 2012 Oct 8. PMID:23043329[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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