Abstract
We examined some in silico approaches to identify Akt (protein kinase B) inhibitors. Experimental validation of selected compounds was achieved using a fluorescence-based enzymatic assay and a substrate phosphorylation assay involving the protein GSK-3. We report on success and failure obtained by using several strategies including FlexX, GOLD, and CSCORE, where the 100-200 top-scoring compounds from a 50000-compound library were experimentally tested. This study led to the identification of low micromolar Akt1 inhibitors.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / chemistry
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Binding Sites
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Databases, Factual
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Enzyme Inhibitors / chemistry*
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Glycogen Synthase Kinase 3 / chemistry
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Glycogen Synthase Kinase 3 beta
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Indazoles / chemistry
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Isoquinolines / chemistry
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Models, Molecular
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Peptide Fragments / chemistry
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Phosphorylation
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Protein Conformation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins c-akt
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Quantitative Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Indazoles
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Isoquinolines
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Peptide Fragments
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Proto-Oncogene Proteins
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Adenosine Triphosphate
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Glycogen Synthase Kinase 3 beta
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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glycogen synthase kinase 3 alpha