4ixf: Difference between revisions
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==pcDHFR-269 F69N variant== | |||
=== | <StructureSection load='4ixf' size='340' side='right' caption='[[4ixf]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ixf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IXF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IXF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IXF:N~6~-METHYL-N~6~-[4-(PROPAN-2-YL)PHENYL]PYRIDO[2,3-D]PYRIMIDINE-2,4,6-TRIAMINE'>IXF</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3cd2|3cd2]], [[4ixe|4ixe]], [[4ixg|4ixg]]</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=4ixf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ixf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ixf RCSB], [http://www.ebi.ac.uk/pdbsum/4ixf PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg) and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogs. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. | |||
Design, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles.,Gangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V J Med Chem. 2013 Apr 29. PMID:23627352<ref>PMID:23627352</ref> | |||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Pneumocystis carinii]] | [[Category: Pneumocystis carinii]] | ||
[[Category: Cody, V | [[Category: Cody, V]] | ||
[[Category: Oxidoreductase-inhibitor complex]] | [[Category: Oxidoreductase-inhibitor complex]] | ||
[[Category: Pcdhfr-269-nadph f69n ternary complex]] | [[Category: Pcdhfr-269-nadph f69n ternary complex]] | ||
[[Category: Reductase]] | [[Category: Reductase]] | ||
Revision as of 15:53, 21 December 2014
pcDHFR-269 F69N variantpcDHFR-269 F69N variant
Structural highlights
Publication Abstract from PubMedOpportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg) and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogs. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. Design, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles.,Gangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V J Med Chem. 2013 Apr 29. PMID:23627352[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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