Abstract
DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.
Keywords:
DYRK1A; Docking; Inhibitor; MAO-A; Pharmacophore; SAR; β-Carboline.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carbolines / chemical synthesis
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Carbolines / chemistry*
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Carbolines / pharmacology*
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Dyrk Kinases
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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Software
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Structure-Activity Relationship
Substances
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Carbolines
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Ligands
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Protein Kinase Inhibitors
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases