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| | ==Structure Guided Development of Novel Thymidine Mimetics targeting Pseudomonas aeruginosa Thymidylate Kinase: from Hit to Lead Generation== | | ==Structure Guided Development of Novel Thymidine Mimetics targeting Pseudomonas aeruginosa Thymidylate Kinase: from Hit to Lead Generation== |
| - | <StructureSection load='3uxm' size='340' side='right' caption='[[3uxm]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='3uxm' size='340' side='right'caption='[[3uxm]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3uxm]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_pao1 Pseudomonas aeruginosa pao1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UXM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UXM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3uxm]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UXM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UXM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0DN:5-DEOXY-5-FLUOROTHYMIDINE'>0DN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3uwk|3uwk]], [[3uwo|3uwo]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0DN:5-DEOXY-5-FLUOROTHYMIDINE'>0DN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PA2962, tmk ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 Pseudomonas aeruginosa PAO1])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3uxm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uxm OCA], [https://pdbe.org/3uxm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uxm RCSB], [https://www.ebi.ac.uk/pdbsum/3uxm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uxm ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3uxm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uxm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uxm RCSB], [http://www.ebi.ac.uk/pdbsum/3uxm PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KTHY_PSEAE KTHY_PSEAE]] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity). | + | [https://www.uniprot.org/uniprot/KTHY_PSEAE KTHY_PSEAE] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity). |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Thymidylate kinase (TMK) is a potential chemotherapeutic target because it is directly involved in the synthesis of an essential component, thymidine triphosphate, in DNA replication. All reported TMK inhibitors are thymidine analogues, which might retard their development as potent therapeutics due to cell permeability and off-target activity against human TMK. A small molecule hit (1, IC(50) = 58 muM), which has reasonable inhibition potency against Pseudomonas aeruginosa TMK (PaTMK), was identified by the analysis of the binding mode of thymidine or TP(5)A in a PaTMK homology model. This hit (1) was cocrystallized with PaTMK, and several potent PaTMK inhibitors (leads, 46, 47, 48, and 56, IC(50) = 100-200 nM) were synthesized using computer-aided design approaches including virtual synthesis/screening, which was used to guide the design of inhibitors. The binding mode of the optimized leads in PaTMK overlaps with that of other bacterial TMKs but not with human TMK, which shares few common features with the bacterial enzymes. Therefore, the optimized TMK inhibitors described here should be useful for the development of antibacterial agents targeting TMK without undesired off-target effects. In addition, an inhibition mechanism associated with the LID loop, which mimics the process of phosphate transfer from ATP to dTMP, was proposed based on X-ray cocrystal structures, homology models, and structure-activity relationship results.
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| - | Structure Guided Development of Novel Thymidine Mimetics Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to Lead Generation.,Choi JY, Plummer MS, Starr J, Desbonnet CR, Soutter H, Chang J, Miller JR, Dillman K, Miller AA, Roush WR J Med Chem. 2012 Jan 26;55(2):852-70. Epub 2012 Jan 13. PMID:22243413<ref>PMID:22243413</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| | ==See Also== | | ==See Also== |
| - | *[[Thymidylate kinase|Thymidylate kinase]] | + | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] |
| - | == References ==
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| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Pseudomonas aeruginosa pao1]] | + | [[Category: Large Structures]] |
| - | [[Category: DTMP kinase]] | + | [[Category: Pseudomonas aeruginosa PAO1]] |
| - | [[Category: Chang, J]] | + | [[Category: Chang J]] |
| - | [[Category: Choi, J Y]] | + | [[Category: Choi JY]] |
| - | [[Category: Desbonnet, C R]] | + | [[Category: Desbonnet CR]] |
| - | [[Category: Dillman, K]] | + | [[Category: Dillman K]] |
| - | [[Category: Miller, A A]] | + | [[Category: Miller AA]] |
| - | [[Category: Miller, J R]] | + | [[Category: Miller JR]] |
| - | [[Category: Plummer, M S]] | + | [[Category: Plummer MS]] |
| - | [[Category: Roush, W R]] | + | [[Category: Roush WR]] |
| - | [[Category: Soutter, H H]] | + | [[Category: Soutter HH]] |
| - | [[Category: Starr, J]] | + | [[Category: Starr J]] |
| - | [[Category: Thymidine triphosphate]]
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| - | [[Category: Thymidylate kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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