2nq8: Difference between revisions

Revision as of 19:09, 21 February 2008

Malarial enoyl acyl ACP reductase bound with INH-NAD adduct

OverviewOverview

The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC50 values of <200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.

About this StructureAbout this Structure

2NQ8 is a Protein complex structure of sequences from Plasmodium falciparum with as ligand. Full crystallographic information is available from OCA.

ReferenceReference

X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy., Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW, Nkrumah LJ, Valderramos JC, Yu M, Kumar TR, Valderramos SG, Jacobs WR Jr, Schiehser GA, Jacobus DP, Fidock DA, Sacchettini JC, J Biol Chem. 2007 Aug 31;282(35):25436-44. Epub 2007 Jun 13. PMID:17567585

Page seeded by OCA on Thu Feb 21 18:09:40 2008

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OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-The X-ray crystal structures of five triclosan analogs, in addition to, that of the isoniazid-NAD adduct, are described in relation to their, integral role in the design of potent inhibitors of the malarial enzyme, Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many, of the novel 5-substituted analogs exhibit low micromolar potency against, in vitro cultures of drug-resistant and drug-sensitive strains of the P., falciparum parasite and inhibit purified PfENR enzyme with IC50 values &lt;, 200 nM. This study has significantly expanded the knowledge base with, regard to the structure-activity relationship (SAR) of triclosan, while, affording gains against cultured parasites and purified PfENR enzyme. In, contrast to a recent report in the literature, these results demonstrate, the ability to improve the in vitro potency of triclosan significantly by, replacing the suboptimal 5-chloro group with larger hydrophobic moieties., The biological and X-ray crystallographic data, thus, demonstrate the, flexibility of the active site and point to future rounds of optimization, to improve compound potency against purified enzyme and intracellular, Plasmodium parasites.
+The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC50 values of &lt;200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-X-ray structural analysis of plasmodium falciparum enoyl acyl carrier protein reductase as a pathway towards the optimization of triclosan antimalarial efficacy., Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW, Nkrumah LJ, Valderramos JC, Yu M, Kumar TR, Valderramos SG, Jacobs WR Jr, Schiehser GA, Jacobus DP, Fidock DA, Sacchettini JC, J Biol Chem. 2007 Jun 13;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17567585 17567585]
+X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy., Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW, Nkrumah LJ, Valderramos JC, Yu M, Kumar TR, Valderramos SG, Jacobs WR Jr, Schiehser GA, Jacobus DP, Fidock DA, Sacchettini JC, J Biol Chem. 2007 Aug 31;282(35):25436-44. Epub 2007 Jun 13. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17567585 17567585]
 [[Category: Plasmodium falciparum]]
 [[Category: Protein complex]]
-[[Category: Fidock, D.A.]]
+[[Category: Fidock, D A.]]
-[[Category: Freundlich, J.S.]]
+[[Category: Freundlich, J S.]]
-[[Category: Jacobus, D.P.]]
+[[Category: Jacobus, D P.]]
-[[Category: Jr., W.R.Jacobs.]]
+[[Category: Jr., W R.Jacobs.]]
 [[Category: Karagyozov, L.]]
 [[Category: Kuo, M.]]
 [[Category: Lucumi, E.]]
-[[Category: Sacchettini, J.C.]]
+[[Category: Sacchettini, J C.]]
-[[Category: Schiehser, G.A.]]
+[[Category: Schiehser, G A.]]
-[[Category: Tsai, H.C.]]
+[[Category: Tsai, H C.]]
-[[Category: Valderramos, J.C.]]
+[[Category: Valderramos, J C.]]
 [[Category: Yu, M.]]
 [[Category: ZID]]
 [[Category: pfenr; inh; malaria]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:02:31 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:09:40 2008''