title: Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors.
abstract: Human 5-lipoxygenase (5-LOX) is one of the key anti-inflammatory drug targets due to its key role in leukotrienes biosynthesis. We have built a model for the active conformation of human 5-LOX using comparative modeling, docking of known inhibitors, and molecular dynamics simulation. Using this model, novel 5-LOX inhibitors were identified by virtual screen. Of the 105 compounds tested in a cell-free assay, 30 have IC(50) values less than 100 μM and 11 less than 10 μM with the strongest inhibition of 620 nM. Compounds 4, 7, and 11 showed strong inhibition activity in the human whole blood (HWB) assay with IC(50) values of 8.6, 9.7, 8.1 μM, respectively. Moreover, compounds 4 and 7 were also found to inhibit microsomal prostaglandin E synthase (mPGES)-1 with micromolar IC(50) values, similar to licofelone, a dual functional inhibitor of 5-LOX/mPGES-1. The compounds reported here provide new scaffolds for anti-inflammatory drug design.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Wu
authors.forename: Chong
authors.initials: C
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood / Q000737:chemistry*; D002474:Cell-Free System; D016208:Databases, Factual; D015232:Dinoprostone / Q000097:blood; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000097:blood; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D056004:Molecular Dynamics Simulation; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D011487:Protein Conformation; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D011994:Recombinant Proteins; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; C088092:licofelone