Structural insights into human 5-lipoxygenase inhibition: combined ligand-based and target-based approach.
The human 5-LOX enzyme and its interaction with competitive inhibitors were investigated by means of a combined ligand-based and target-based approach. First, a pharmacophore model was generated for 16 non redox 5-LOX inhibitors with Catalyst (HipHop module). It includes two hydrophobic groups, an aromatic ring, and two hydrogen bond acceptors. The 3D structure of human 5-LOX was then modeled based on the crystal structure of rabbit 15-LOX, and the binding modes of representative ligands were studied by molecular docking. Confrontation of the docking results with the pharmacophore model allowed the weighting of the pharmacophoric features and the integration of structural information. This led to the proposal of an interaction model inside the 5-LOX active site, consisting of four major and two secondary interaction points: on one hand, two hydrophobic groups, an aromatic ring, and a hydrogen bond acceptor, and, on the other hand, an acidic moiety and an additional hydrogen bond acceptor.
Charlier
Caroline
C
Laboratory of Structural Biological Chemistry, University of Namur, FUNDP, 61, rue de Bruxelles, B-5000 Namur, Belgium.
Hénichart
Jean-Pierre
JP
Durant
François
F
Wouters
Johan
J
D000595:Amino Acid Sequence; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D003198:Computer Simulation; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase