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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2005-1-20
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pubmed:abstractText |
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AnthonyRachelR,
pubmed-author:CarrMaria GMG,
pubmed-author:CarrRobin A ERA,
pubmed-author:CleasbyAnneA,
pubmed-author:CongreveMiles SMS,
pubmed-author:CurryJayneJ,
pubmed-author:DavisDeborah JDJ,
pubmed-author:DevineLindsay ALA,
pubmed-author:FredericksonMartynM,
pubmed-author:GillAdrian LAL,
pubmed-author:JhotiHarrenH,
pubmed-author:MurrayChristopher WCW,
pubmed-author:O'ReillyMarcM,
pubmed-author:PadovaAlessandroA,
pubmed-author:SeaversLisa C ALC,
pubmed-author:TisiDominicD,
pubmed-author:WalkerMargaret TMT,
pubmed-author:WoodheadAndrew JAJ,
pubmed-author:WoodheadSteven JSJ
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pubmed:issnType |
Print
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pubmed:day |
27
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
414-26
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15658855-Aminopyridines,
pubmed-meshheading:15658855-Cell Line, Tumor,
pubmed-meshheading:15658855-Crystallography, X-Ray,
pubmed-meshheading:15658855-Databases, Factual,
pubmed-meshheading:15658855-Drug Design,
pubmed-meshheading:15658855-Enzyme Inhibitors,
pubmed-meshheading:15658855-Humans,
pubmed-meshheading:15658855-Indoles,
pubmed-meshheading:15658855-Ligands,
pubmed-meshheading:15658855-Models, Molecular,
pubmed-meshheading:15658855-Molecular Structure,
pubmed-meshheading:15658855-Protein Binding,
pubmed-meshheading:15658855-Quantitative Structure-Activity Relationship,
pubmed-meshheading:15658855-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2005
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pubmed:articleTitle |
Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.
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pubmed:affiliation |
Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. a.gill@astex-technology.com
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pubmed:publicationType |
Journal Article
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