1tsl: Difference between revisions

Revision as of 16:16, 21 February 2008

L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR

OverviewOverview

Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.

About this StructureAbout this Structure

1TSL is a Single protein structure of sequence from Lactobacillus casei with and as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Structure-based design of inhibitors specific for bacterial thymidylate synthase., Stout TJ, Tondi D, Rinaldi M, Barlocco D, Pecorari P, Santi DV, Kuntz ID, Stroud RM, Shoichet BK, Costi MP, Biochemistry. 1999 Feb 2;38(5):1607-17. PMID:9931028

Page seeded by OCA on Thu Feb 21 15:16:52 2008

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OCA

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 ==Overview==
-Thymidylate synthase is an attractive target for antiproliferative drug, design because of its key role in the synthesis of DNA. As such, the, enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious, disease. In practice, TS is highly conserved across species, and it has, proven to be difficult to develop inhibitors that are selective for, microbial TS enzymes over the human enzyme. Using the structure of TS from, Lactobacillus casei in complex with the nonsubstrate analogue, phenolphthalein, inhibitors were designed to take advantage of features of, the bacterial enzyme that differ from those of the human enzyme. Upon, synthesis and testing, these inhibitors were found to be up to 40-fold, selective for the bacterial enzyme over the human enzyme. The crystal, structures of two of these inhibitors in complex with TS suggested the, design of further compounds. Subsequent synthesis and testing showed that, these second-round compounds inhibit the bacterial enzyme at, sub-micromolar concentrations, while the human enzyme was not inhibited at, detectable levels (selectivities of 100-1000-fold or greater). Although, these inhibitors share chemical similarities, X-ray crystal structures, reveal that the analogues bind to the enzyme in substantially different, orientations. Site-directed mutagenesis experiments suggest that the, individual inhibitors may adopt multiple configurations in their complexes, with TS.
+Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.
 ==About this Structure==
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 [[Category: Single protein]]
 [[Category: Thymidylate synthase]]
-[[Category: Stout, T.J.]]
+[[Category: Stout, T J.]]
-[[Category: Stroud, R.M.]]
+[[Category: Stroud, R M.]]
 [[Category: A15]]
 [[Category: PO4]]
@@ Line 23: / Line 23: @@
 [[Category: structure-based drug design]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:02:38 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:16:52 2008''