2ohm: Difference between revisions

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==Overview==

This paper describes an application of fragment screening to the aspartyl, protease enzyme, beta-secretase (BACE-1), using high throughput X-ray, crystallography. Three distinct chemotypes were identified by X-ray, crystallography as binding to the catalytic aspartates either via an, aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic, hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the, millimolar range but were of interest because most of them displayed, relatively good ligand efficiencies. The aminoheterocycles exhibited a, novel recognition motif that has not been seen before with aspartic, proteases. Virtual screening around this motif identified an aminopyridine, with increased potency and attractive growth points for further, elaboration using structure-based drug design. The companion paper, illustrates how sub-micromolar inhibitors were developed starting from, this fragment.

This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.

==About this Structure==

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==Reference==

Application of ~~Fragment Screening~~ by X-ray ~~Crystallography~~ to beta-~~Secretase~~., Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N, J Med Chem. 2007 Feb 22;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17315856 17315856]

Application of fragment screening by X-ray crystallography to beta-secretase., Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N, J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17315856 17315856]

[[Category: Homo sapiens]]

[[Category: Memapsin 2]]

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[[Category: zymogen]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:18:36 2008''

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@@ Line 4: / Line 4: @@
 ==Overview==
-This paper describes an application of fragment screening to the aspartyl, protease enzyme, beta-secretase (BACE-1), using high throughput X-ray, crystallography. Three distinct chemotypes were identified by X-ray, crystallography as binding to the catalytic aspartates either via an, aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic, hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the, millimolar range but were of interest because most of them displayed, relatively good ligand efficiencies. The aminoheterocycles exhibited a, novel recognition motif that has not been seen before with aspartic, proteases. Virtual screening around this motif identified an aminopyridine, with increased potency and attractive growth points for further, elaboration using structure-based drug design. The companion paper, illustrates how sub-micromolar inhibitors were developed starting from, this fragment.
+This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-Application of Fragment Screening by X-ray Crystallography to beta-Secretase., Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N, J Med Chem. 2007 Feb 22;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17315856 17315856]
+Application of fragment screening by X-ray crystallography to beta-secretase., Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N, J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17315856 17315856]
 [[Category: Homo sapiens]]
 [[Category: Memapsin 2]]
@@ Line 31: / Line 31: @@
 [[Category: zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:25:18 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:18:36 2008''