Caractérisation structurale de la 5-lipoxygénase humaine et de son inhibition: support à la conception rationnelle d'inhibiteurs mixtes 5-LOX-COX-2

Student thesis: Doc typesDoctor of Sciences

Abstract

Dual 5-LOX/COX-2 inhibitors, acting on both major arachidonic acid metabolic pathways, are potent non-steroidal anti-inflammatory agents, with a reduced gastro-intestinal toxicity and fewer allergic adverse reactions. Moreover, they are promising in the treatment of several cancers. Whereas COX-2 has already been extensively studied, little structural or mechanistic information is available regarding human 5-LOX. Therefore, we focussed on this enzyme and characterized its 3D structure as well as its interaction with non redox inhibitors in order to help the design of dual 5-LOX/COX-2 inhibitors. Firstly, comparison of non redox 5-LOX inhibitors from the literature led to the generation of a five-point pharmacophore model. The 3D structure of human 5-LOX was then modelled based on the crystal structure of rabbit 15-LOX and, the binding modes of representative ligands were investigated through docking studies. Combination of both ligand-based and target-based approaches allowed the refinement of the pharmacophore hypothesis and led to the proposal of an interaction model for non redox inhibitors inside the 5-LOX active site.
Date of Award15 Feb 2006
Original languageFrench
Awarding Institution
  • University of Namur
SupervisorJohan Wouters (Supervisor), François Durant (Co-Supervisor), Jean-Michel Dogne (Jury), Daniel Vercauteren (Jury), J.P. Hennichart (Jury) & Florence Moureau (Jury)

Keywords

  • interaction model
  • anti-inflammatory
  • dual inhibitors
  • arachidonic acid

Cite this

Caractérisation structurale de la 5-lipoxygénase humaine et de son inhibition: support à la conception rationnelle d'inhibiteurs mixtes 5-LOX-COX-2
Charlier, C. (Author). 15 Feb 2006

Student thesis: Doc typesDoctor of Sciences