4HLC

Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 5

4HLC の概要

• エントリーDOI: 10.2210/pdb4hlc/pdb
• 関連するPDBエントリー: 4GFD 4GSY 4HDC 4HEJ 4HLD
• 分子名称: Thymidylate kinase, 4-{[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]sulfonyl}-2-(3-methylphenoxy)benzoic acid (3 entities in total)
• 機能のキーワード: tmk, kinase, thymidylate kinase, mrsa, pipiridine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Staphylococcus aureus subsp. aureus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47908.24

構造登録者

Boriack-Sjodin, A.,Olivier, N. (登録日: 2012-10-16, 公開日: 2012-10-31, 最終更新日: 2024-04-03)

主引用文献

Martinez-Botella, G.,Loch, J.T.,Green, O.M.,Kawatkar, S.P.,Olivier, N.B.,Boriack-Sjodin, P.A.,Keating, T.A.
Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).
Bioorg.Med.Chem.Lett., 23:169-173, 2013

PubMed Abstract: 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.

PubMed: 23206863
DOI: 10.1016/j.bmcl.2012.10.128

実験手法

X-RAY DIFFRACTION (1.55 Å)