Abstract
Results from molecular docking calculations and Grid mapping laid the foundations for a structure-based optimization approach to improve the biological properties of pyrazolo-pyrimidine derivatives in terms of inhibition of Abl enzymatic activity and antiproliferative properties toward human leukemia cells. Insertion of halogen substituents with various substitution patterns, suggested by simulations, led to a significant improvement of leukemia cell growth inhibition and to an increase up to 1 order of magnitude of the affinity toward Abl.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Fusion Proteins, bcr-abl
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Humans
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Leukemia
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Models, Molecular
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Pyrazoles
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Pyrimidines
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl