In situ click chemistry generation of cyclooxygenase-2 inhibitors

Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isof...

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Bibliographic Details
Published in:Nature communications Vol. 8; no. 1; pp. 1 - 14
Main Authors: Bhardwaj, Atul, Kaur, Jatinder, Wuest, Melinda, Wuest, Frank
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 23.02.2017
Nature Publishing Group
Nature Portfolio
Subjects:
631/154/309/2144
631/92/96
639/638/309/2144
639/638/92/96
Animals
Anti-inflammatory agents
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Binding sites
Biosynthesis
Carrageenan
Chemical synthesis
Chemistry
Click Chemistry - methods
COX-2 inhibitors
Cyclooxygenase 1 - chemistry
Cyclooxygenase 1 - genetics
Cyclooxygenase 1 - metabolism
Cyclooxygenase 2 - chemistry
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Cyclooxygenase 2 Inhibitors - chemical synthesis
Cyclooxygenase 2 Inhibitors - pharmacology
Cyclooxygenase-1
Cyclooxygenase-2
Drug Design
Edema - chemically induced
Edema - drug therapy
Edema - enzymology
Edema - pathology
Enzymes
Female
Gene Expression
Heart attacks
Hindlimb
Humanities and Social Sciences
Humans
Inflammation
Inhibitors
Kinetics
Molecular Docking Simulation
multidisciplinary
Nonsteroidal anti-inflammatory drugs
Pain
Pharmaceuticals
Protein Structure, Secondary
Proteins
Pyrazoles - chemical synthesis
Pyrazoles - pharmacology
Rats
Science
Science (multidisciplinary)
Side effects
Structure-Activity Relationship
Thermodynamics
Triazoles - chemical synthesis
Triazoles - pharmacology
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-016-0009-6