4lek
From Proteopedia
(Difference between revisions)
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| - | + | ==Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines== | |
| - | + | <StructureSection load='4lek' size='340' side='right' caption='[[4lek]], [[Resolution|resolution]] 1.70Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[4lek]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LEK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LEK FirstGlance]. <br> | |
| - | ==Function== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1DN:7-[5,6-DIMETHOXY-2-(1,3-THIAZOL-2-YL)-1H-BENZIMIDAZOL-1-YL]QUINAZOLINE-2,4-DIAMINE'>1DN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lae|4lae]], [[4lag|4lag]], [[4lah|4lah]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></td></tr> | ||
| + | <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=4lek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lek OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lek RCSB], [http://www.ebi.ac.uk/pdbsum/4lek PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
[[http://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | [[http://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 mug/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 mug/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series. | ||
| - | + | Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines.,Lam T, Hilgers MT, Cunningham ML, Kwan BP, Nelson KJ, Brown-Driver V, Ong V, Trzoss M, Hough G, Shaw KJ, Finn J J Med Chem. 2014 Feb 13;57(3):651-68. doi: 10.1021/jm401204g. Epub 2014 Jan 16. PMID:24428639<ref>PMID:24428639</ref> | |
| - | + | ||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | ||
| - | + | == References == | |
| - | == | + | <references/> |
| - | + | __TOC__ | |
| + | </StructureSection> | ||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
| - | [[Category: Hilgers, M T | + | [[Category: Hilgers, M T]] |
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
Revision as of 17:18, 24 December 2014
Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines
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