1way: Difference between revisions
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==Overview== | ==Overview== | ||
Fragment screening offers an alternative to traditional screening for, discovering new leads in drug discovery programs. This paper describes a, fragment screening methodology based on high throughput X-ray, crystallography. The method is illustrated against five proteins (p38 MAP, kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments, identified have weak potency (>100 microM) but are efficient binders, relative to their size and may therefore represent suitable starting, points for evolution to good quality lead compounds. The examples, illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also, that fragments can induce protein movement. We believe that the method has, great potential for the discovery of novel lead compounds against a range, of targets, and the companion paper illustrates how lead compounds have, been identified for p38 MAP kinase starting from fragments such as those, described in this paper. | Fragment screening offers an alternative to traditional screening for, discovering new leads in drug discovery programs. This paper describes a, fragment screening methodology based on high throughput X-ray, crystallography. The method is illustrated against five proteins (p38 MAP, kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments, identified have weak potency (>100 microM) but are efficient binders, relative to their size and may therefore represent suitable starting, points for evolution to good quality lead compounds. The examples, illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also, that fragments can induce protein movement. We believe that the method has, great potential for the discovery of novel lead compounds against a range, of targets, and the companion paper illustrates how lead compounds have, been identified for p38 MAP kinase starting from fragments such as those, described in this paper. | ||
==Disease== | |||
Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: vitamin k]] | [[Category: vitamin k]] | ||
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Revision as of 20:42, 12 November 2007
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ACTIVE SITE THROMBIN INHIBITORS
OverviewOverview
Fragment screening offers an alternative to traditional screening for, discovering new leads in drug discovery programs. This paper describes a, fragment screening methodology based on high throughput X-ray, crystallography. The method is illustrated against five proteins (p38 MAP, kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments, identified have weak potency (>100 microM) but are efficient binders, relative to their size and may therefore represent suitable starting, points for evolution to good quality lead compounds. The examples, illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also, that fragments can induce protein movement. We believe that the method has, great potential for the discovery of novel lead compounds against a range, of targets, and the companion paper illustrates how lead compounds have, been identified for p38 MAP kinase starting from fragments such as those, described in this paper.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1WAY is a Protein complex structure of sequences from Homo sapiens with L02 and DMS as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Fragment-based lead discovery using X-ray crystallography., Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H, J Med Chem. 2005 Jan 27;48(2):403-13. PMID:15658854
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Protein complex
- Thrombin
- Cleasby, A.
- Frederickson, M.
- Hartshorn, M.J.
- Jhoti, H.
- Murray, C.W.
- Tickle, I.J.
- DMS
- L02
- Acute phase
- Blood coagulation
- Calcium-binding
- Direct protein sequencing
- Disease mutation
- Gamma-carboxyglutamic acid
- Glycoprotein
- Hydrolase
- Kringle
- Plasma
- Polymorphism
- Protease
- Serine protease
- Vitamin k