4QGA
S.aureus TMK in complex with potent inhibitor compound 19, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]METHYL}BENZOIC ACID
Summary for 4QGA
| Entry DOI | 10.2210/pdb4qga/pdb |
| Related | 4QGA 4QGF 4QGG 4QGH |
| Descriptor | Thymidylate kinase, 2-(3-chlorophenoxy)-3-fluoro-4-{[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]methyl}benzoic acid (3 entities in total) |
| Functional Keywords | transferase/transferase inhibitor kinase, thymidine monphosphate, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Staphylococcus aureus subsp. aureus |
| Total number of polymer chains | 2 |
| Total formula weight | 47884.99 |
| Authors | Olivier, N.B. (deposition date: 2014-05-22, release date: 2014-06-11, Last modification date: 2024-02-28) |
| Primary citation | Kawatkar, S.P.,Keating, T.A.,Olivier, N.B.,Breen, J.N.,Green, O.M.,Guler, S.Y.,Hentemann, M.F.,Loch, J.T.,McKenzie, A.R.,Newman, J.V.,Otterson, L.G.,Martinez-Botella, G. Antibacterial inhibitors of gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region. J.Med.Chem., 57:4584-4597, 2014 Cited by PubMed Abstract: Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 μg/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses. PubMed: 24828090DOI: 10.1021/jm500463c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
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