3jsu: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image: | ==Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP== | ||
<StructureSection load='3jsu' size='340' side='right' caption='[[3jsu]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3jsu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JSU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JSU FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KA5:5-CHLORO-N~6~-(2,5-DIMETHOXYBENZYL)QUINAZOLINE-2,4,6-TRIAMINE'>KA5</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1j3k|1j3k]], [[1j3j|1j3j]], [[1j3i|1j3i]], [[3dg8|3dg8]], [[3dga|3dga]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR-TS, V1/S ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 Plasmodium falciparum])</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=3jsu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jsu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3jsu RCSB], [http://www.ebi.ac.uk/pdbsum/3jsu PDBsum]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/js/3jsu_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent. | |||
Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.,Nzila A, Rottmann M, Chitnumsub P, Kiara SM, Kamchonwongpaisan S, Maneeruttanarungroj C, Taweechai S, Yeung BK, Goh A, Lakshminarayana SB, Zou B, Wong J, Ma NL, Weaver M, Keller TH, Dartois V, Wittlin S, Brun R, Yuthavong Y, Diagana TT Antimicrob Agents Chemother. 2010 Jun;54(6):2603-10. Epub 2010 Mar 29. PMID:20350951<ref>PMID:20350951</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: Plasmodium falciparum]] | [[Category: Plasmodium falciparum]] | ||
[[Category: Chitnumsub, P | [[Category: Chitnumsub, P]] | ||
[[Category: Diagana, T T | [[Category: Diagana, T T]] | ||
[[Category: Kamchonwongpaisan, S | [[Category: Kamchonwongpaisan, S]] | ||
[[Category: Maneeruttanarungroj, C | [[Category: Maneeruttanarungroj, C]] | ||
[[Category: Yuthavong, Y | [[Category: Yuthavong, Y]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Rossmann fold]] | [[Category: Rossmann fold]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 12:31, 8 December 2014
Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMPQuadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedDrug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent. Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.,Nzila A, Rottmann M, Chitnumsub P, Kiara SM, Kamchonwongpaisan S, Maneeruttanarungroj C, Taweechai S, Yeung BK, Goh A, Lakshminarayana SB, Zou B, Wong J, Ma NL, Weaver M, Keller TH, Dartois V, Wittlin S, Brun R, Yuthavong Y, Diagana TT Antimicrob Agents Chemother. 2010 Jun;54(6):2603-10. Epub 2010 Mar 29. PMID:20350951[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||