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

Author(s)

Viviani, Lucas G. ; Iijima, Thais S. ; Piccirillo, Erika ; Rezende, Leandro ; Alegria, Thiago G. P. ; Netto, Luis Eduardo S. ; T-do Amaral, Antonia ; Miyamoto, Sayuri

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 68, n. 1, p. 17-pg., 2024-12-19.

Abstract

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 (similar to 8 x 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 mu M) and 13 (Ki = 15.1 +/- 7.6 mu M), 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. (AU)

• FAPESP's process: 21/10514-8 - Identification and selection of inhibitors and/or activators of enzymes involved in the formation and detoxification of oxidized lipids
• Grantee: Lucas Gasparello Viviani
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC