Identification of novel human 15-lipoxygenase-2 (h15-LOX-2) inhibitors using a virtual screening approach

The human 15-lipoxygenase-2 (h15-LOX-2) is a non-heme iron-containing enzyme that catalyzes the regio- and stereospecific oxygenation of polyunsaturated fatty acids, mainly arachidonic acid, and is implicated in the biosynthesis of pro- and anti-inflammatory lipid mediators. The biological roles of h15-LOX-2 have not been completely unveiled, but it has been suggested that high expression levels of h15-LOX-2 are related to the pathogenesis of atherosclerosis and of some types of cancer. Inhibitors of h15-LOX-2 might be helpful for a deeper understanding of its roles in physiological and pathophysiological processes, in addition to representing potential drug candidates for treating human diseases. Nevertheless, only a few h15-LOX-2 inhibitors have been reported in the literature to date. Here, aiming to search for novel h15-LOX-2 inhibitors, we used a virtual screening (VS) approach, consisting of four consecutive filters (shape-based matching, 2D structural “dissimilarity”, docking, and careful visual inspection), which were applied to a “curated” version of the ZINC database, pre-filtered for potential drug-like compounds. Six novel h15- LOX-2 inhibitors, with inhibitory potencies in the micromolar range, were identified. K _i values were determined for two inhibitors, compounds 10 [K _i = (16.4 ± 8.1) μM] and 13 [K _i = (15.1 ± 7.6) μM], which showed a mixed-type mechanism of inhibition. According to docking predictions, the identified inhibitors occupy the more solvent-exposed arm of the U-shaped h15-LOX-2 active site’s cavity, possibly blocking the access of the substrate to the active site. The identified inhibitors are structurally different from the few h15-LOX-2 inhibitors reported in the literature, in addition to fulfilling drug-like criteria. Overall, our results provide a valuable contribution to the search for novel inhibitors of h15-LOX-2, a so-far underexploited target enzyme.