1t2d: Difference between revisions

Revision as of 16:09, 21 February 2008

Plasmodium falciparum lactate dehydrogenase complexed with NAD+ and oxalate

OverviewOverview

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.

About this StructureAbout this Structure

1T2D is a Single protein structure of sequence from Plasmodium falciparum with , and as ligands. Active as L-lactate dehydrogenase, with EC number 1.1.1.27 Full crystallographic information is available from OCA.

ReferenceReference

Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity., Cameron A, Read J, Tranter R, Winter VJ, Sessions RB, Brady RL, Vivas L, Easton A, Kendrick H, Croft SL, Barros D, Lavandera JL, Martin JJ, Risco F, Garcia-Ochoa S, Gamo FJ, Sanz L, Leon L, Ruiz JR, Gabarro R, Mallo A, Gomez de las Heras F, J Biol Chem. 2004 Jul 23;279(30):31429-39. Epub 2004 Apr 26. PMID:15117937

Page seeded by OCA on Thu Feb 21 15:09:09 2008

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OCA

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-[[Image:1t2d.jpg|left|200px]]<br /><applet load="1t2d" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1t2d.jpg|left|200px]]<br /><applet load="1t2d" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1t2d, resolution 1.10&Aring;" />
 '''Plasmodium falciparum lactate dehydrogenase complexed with NAD+ and oxalate'''<br />
 ==Overview==
-Plasmodium falciparum, the causative agent of malaria, relies extensively, on glycolysis coupled with homolactic fermentation during its blood-borne, stages for energy production. Selective inhibitors of the parasite lactate, dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially, provide a route to new antimalarial drugs directed against a novel, molecular target. A series of heterocyclic, azole-based compounds are, described that preferentially inhibit P. falciparum LDH at sub-micromolar, concentrations, typically at concentrations about 100-fold lower than, required for human lactate dehydrogenase inhibition. Crystal structures, show these competitive inhibitors form a network of interactions with, amino acids within the active site of the enzyme, stacking alongside the, nicotinamide ring of the NAD(+) cofactor. These compounds display modest, activity against parasitized erythrocytes, including parasite strains with, known resistance to existing anti-malarials and against Plasmodium berghei, in BALB/c mice. Initial toxicity data suggest the azole derivatives have, generally low cytotoxicity, and preliminary pharmoco-kinetic data show, favorable bioavailability and circulation times. These encouraging results, suggest that further enhancement of these structures may yield candidates, suitable for consideration as new therapeutics for the treatment of, malaria. In combination these studies also provide strong support for the, validity of targeting the Plasmodium glycolytic pathway and, in, particular, LDH in the search for novel anti-malarials.
+Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
 ==About this Structure==
-T2D is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with OXL, NAD and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1T2D OCA].
+T2D is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=OXL:'>OXL</scene>, <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T2D OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Barros, D.]]
-[[Category: Brady, R.L.]]
+[[Category: Brady, R L.]]
 [[Category: Cameron, A.]]
-[[Category: Croft, S.L.]]
+[[Category: Croft, S L.]]
 [[Category: Easton, A.]]
 [[Category: Gabarro, R.]]
-[[Category: Gamo, F.J.]]
+[[Category: Gamo, F J.]]
 [[Category: Garcia-Ochoa, S.]]
-[[Category: Heras, F.G.De.Las.]]
+[[Category: Heras, F G.De Las.]]
 [[Category: Kendrick, H.]]
-[[Category: Lavandera, J.L.]]
+[[Category: Lavandera, J L.]]
 [[Category: Leon, L.]]
 [[Category: Mallo, A.]]
-[[Category: Martin, J.J.]]
+[[Category: Martin, J J.]]
 [[Category: Read, J.]]
 [[Category: Risco, F.]]
-[[Category: Ruiz, J.R.]]
+[[Category: Ruiz, J R.]]
 [[Category: Sanz, L.]]
-[[Category: Sessions, R.B.]]
+[[Category: Sessions, R B.]]
 [[Category: Tranter, R.]]
 [[Category: Vivas, L.]]
-[[Category: Winter, V.J.]]
+[[Category: Winter, V J.]]
 [[Category: GOL]]
 [[Category: NAD]]
@@ Line 41: / Line 41: @@
 [[Category: ternary complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 02:56:14 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:09 2008''