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bioRxiv · 10.1101/2024.07.21.604444

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

Viviani, L. G.·Iijima, T. S.·Piccirillo, E.·de Rezende, L.·Alegria, T. G. P.·Netto, L. E. S.·do Amaral, A. T.·Miyamoto, S.
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Abstract

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. Ki values were determined for two inhibitors, compounds 10 [Ki = (16.4 {+/-} 8.1) M] and 13 [Ki = (15.1 {+/-} 7.6) M], 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 sites 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.

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Viviani, L. G., Iijima, T. S., Piccirillo, E., de Rezende, L., Alegria, T. G. P., Netto, L. E. S., do Amaral, A. T., Miyamoto, S.. 2024-07-21. Identification of novel human 15-lipoxygenase-2 (h15-LOX-2) inhibitors using a virtual screening approach. https://doi.org/10.1101/2024.07.21.604444

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