4HEJ

Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16

Summary for 4HEJ

• Entry DOI: 10.2210/pdb4hej/pdb
• Related: 4GSY 4HDC
• Descriptor: Thymidylate kinase, 5-methyl-1-[(3S)-1-{3-[3-(trifluoromethyl)phenoxy]benzyl}piperidin-3-yl]pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: tmk, inhibitor, tmp, antibacterial, dna repair, kinase, dtmp atp, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Staphylococcus aureus subsp. aureus
• Total number of polymer chains: 2
• Total formula weight: 47368.63

Authors

Martinez-Botella, G.,Breen, J.,Duffy, J.,Dumas, J.,Geng, B.,Gowers, I.,Green, O.,Guler, S.,Hentemann, M.,Hernandez-Juan, F.,Joseph-McCarthy, D.,Kawatkar, S.,Larsen, N.,Lazari, O.,Loch, J.,Macritchie, J. (deposition date: 2012-10-03, release date: 2012-10-24, Last modification date: 2024-02-28)

Primary citation

Martinez-Botella, G.,Breen, J.N.,Duffy, J.E.,Dumas, J.,Geng, B.,Gowers, I.K.,Green, O.M.,Guler, S.,Hentemann, M.F.,Hernandez-Juan, F.A.,Joseph-McCarthy, D.,Kawatkar, S.,Larsen, N.A.,Lazari, O.,Loch, J.T.,Macritchie, J.A.,McKenzie, A.R.,Newman, J.V.,Olivier, N.B.,Otterson, L.G.,Owens, A.P.,Read, J.,Sheppard, D.W.,Keating, T.A.
Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK).
J.Med.Chem., 55:10010-10021, 2012

PubMed Abstract: Thymidylate 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 μg/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.

PubMed: 23043329
DOI: 10.1021/jm3011806

Experimental method

X-RAY DIFFRACTION (2 Å)