Dynamic Modeling of Human 5-Lipoxygenase鈥揑nhibitor Interactions Helps To Discover Novel Inhibitors
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文摘
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 IC50 values less than 100 渭M and 11 less than 10 渭M with the strongest inhibition of 620 nM. Compounds 4, 7, and 11 showed strong inhibition activity in the human whole blood (HWB) assay with IC50 values of 8.6, 9.7, 8.1 渭M, respectively. Moreover, compounds 4 and 7 were also found to inhibit microsomal prostaglandin E synthase (mPGES)-1 with micromolar IC50 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.