Dynamic Modeling of Human 5-Lipoxygenase–Inhibitor Interactions Helps To Discover Novel Inhibitors

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 μM and 11 less than 10 μM with the strongest inhibition of 620 nM. Compounds <b>4</b>, <b>7</b>, and <b>11</b> showed strong inhibition activity in the human whole blood (HWB) assay with IC₅₀ values of 8.6, 9.7, 8.1 μM, respectively. Moreover, compounds <b>4</b> and <b>7</b> 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