Molecular docking-guided synthesis of NSAID-glucosamine bioconjugates and their evaluation as COX-1/COX-2 inhibitors with potentially reduced gastric toxicity. Chem Biol Drug Des 2021 Jul;98(1):102-113
Date
05/07/2021Pubmed ID
33955172Pubmed Central ID
PMC8281356DOI
10.1111/cbdd.13855Scopus ID
2-s2.0-85106558172 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1 and COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has been associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. We report herein the conjugation of commonly prescribed NSAIDs to glucosamine hydrochloride and the use of molecular docking to show that addition of the carbohydrate moiety to the parent NSAID can enhance binding in the active site of COX-2. In a preliminary, in vitro screening assay, the diclofenac-glucosamine bioconjugate exhibited 10-fold greater activity toward COX-2, making it an ideal candidate for future in vivo studies. Furthermore, in an intriguing result, we observed that the mefenamic acid-glucosamine bioconjugate displayed enhanced activity toward COX-1 rather than COX-2.
Author List
Jones Lipinski RA, Thillier Y, Morisseau C, Sebastiano CS Jr, Smith BC, Hall CD, Katritzky ARAuthors
Rachel Jones Lipinski Research Scientist I in the Biochemistry department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anti-Inflammatory Agents, Non-SteroidalCatalytic Domain
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase Inhibitors
Diclofenac
Drug Design
Glucosamine
Glycoconjugates
Mefenamic Acid
Molecular Docking Simulation
Protein Binding
Protein Conformation
Stomach
Structure-Activity Relationship
