Abstract
Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology
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Catalytic Domain
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Cyclooxygenase 1 / chemistry
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Cyclooxygenase 1 / metabolism*
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Cyclooxygenase 2 / chemistry
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Cyclooxygenase 2 / metabolism*
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Cyclooxygenase Inhibitors / chemical synthesis
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / metabolism
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Cyclooxygenase Inhibitors / pharmacology
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Drug Design*
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Edema / chemically induced
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Edema / drug therapy
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Female
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Lipoxygenase / chemistry
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Lipoxygenase / metabolism*
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Lipoxygenase Inhibitors / chemical synthesis
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Lipoxygenase Inhibitors / chemistry
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Lipoxygenase Inhibitors / metabolism
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Lipoxygenase Inhibitors / pharmacology
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Male
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Mice
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Models, Molecular
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Structure-Activity Relationship
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Thiazolidines / chemical synthesis
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Thiazolidines / chemistry*
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Thiazolidines / metabolism
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Thiazolidines / pharmacology*
Substances
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Anti-Inflammatory Agents
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Cyclooxygenase Inhibitors
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Lipoxygenase Inhibitors
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Thiazolidines
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Lipoxygenase
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Cyclooxygenase 1
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Cyclooxygenase 2