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Identification of Novel Human 15-Lipoxygenase-2 (h15-LOX-2) Inhibitors Using a Virtual Screening Approach
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-12-19 , DOI: 10.1021/acs.jmedchem.4c01884 Lucas G. Viviani, Thais S. Iijima, Erika Piccirillo, Leandro Rezende, Thiago G. P. Alegria, Luis Eduardo S. Netto, Antonia T.-do Amaral, Sayuri Miyamoto
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-12-19 , DOI: 10.1021/acs.jmedchem.4c01884 Lucas G. Viviani, Thais S. Iijima, Erika Piccirillo, Leandro Rezende, Thiago G. P. Alegria, Luis Eduardo S. Netto, Antonia T.-do Amaral, Sayuri Miyamoto
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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.
更新日期：2024-12-20
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