Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach

The human 15-lipoxygenase-2 (h15-LOX-2) catalyzes mainly the regio- and stereospecific oxygenation of arachidonate to its corresponding hydroperoxide (15(<i>S</i>)-HpETE). h15-LOX-2 is implicated in the biosynthesis of inflammatory lipid mediators and plays a role in the development of atherosclerotic plaques, but it is still underexploited as a drug target. Here, to search for novel h15-LOX-2 inhibitors, we used a virtual screening (VS) approach consisting of shape-based matching, two-dimensional (2D) structural "dissimilarity", docking, and visual inspection filters, which were applied to a "curated" ZINC database (∼8 × 10⁶ compounds). The VS was experimentally validated, and six micromolar-range inhibitors were identified among 13 tested compounds (46.2%). The <i>K_i</i> values could be determined for two inhibitors, compounds <b>10</b> (<i>K_i</i> = 16.4 ± 8.1 μM) and <b>13</b> (<i>K_i</i> = 15.1 ± 7.6 μM), which showed a mixed-type mechanism of inhibition. Overall, the identified inhibitors fulfill drug-like criteria and are structurally novel compared with known h15-LOX-2 inhibitors.