4hld | pdb_00004hld

Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11

spinqualitylabelsall models 4hld, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hld is a 2 chain structure with sequence from Staphylococcus aureus subsp. aureus mrsa252. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 16T Related: 4gfd, 4hdc, 4gsy, 4hej, 4hlc Gene: SAR0483, tmk (Staphylococcus aureus subsp. aureus MRSA252) Activity: dTMP kinase, with EC number 2.7.4.9 Resources: FirstGlance, OCA, RCSB, PDBsum 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate kinase

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