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(S)-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 Ki values could be determined for two inhibitors, compounds 10 (Ki = 16.4 ± 8.1 μM) and 13 (Ki = 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.