4qgf

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32B:2-(3-CHLOROPHENOXY)-3-METHOXY-4-{(1R)-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]PROPYL}BENZOIC+ACID'>32B</scene></td></tr>

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== Publication Abstract from PubMed ==

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 mug/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.

Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure-Activity Relationships and Chiral Preference of a New Hydrophobic Binding Region.,Kawatkar SP, Keating TA, Olivier NB, Breen JN, Green OM, Guler SY, Hentemann MF, Loch JT, McKenzie AR, Newman JV, Otterson LG, Martinez-Botella G J Med Chem. 2014 Jun 3. PMID:24828090<ref>PMID:24828090</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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== References ==

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