| Texto completo | |
| Autor(es): |
Viviani, Lucas G.
;
Iijima, Thais S.
;
Piccirillo, Erika
;
Rezende, Leandro
;
Alegria, Thiago G. P.
;
Netto, Luis Eduardo S.
;
T-do Amaral, Antonia
;
Miyamoto, Sayuri
Número total de Autores: 8
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Journal of Medicinal Chemistry; v. 68, n. 1, p. 17-pg., 2024-12-19. |
| Resumo | |
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) | |
| Processo FAPESP: | 21/10514-8 - Identificação e seleção de inibidores e/ou ativadores de enzimas envolvidas na formação e na detoxificação de lipídeos oxidados |
| Beneficiário: | Lucas Gasparello Viviani |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 13/07937-8 - Redoxoma |
| Beneficiário: | Ohara Augusto |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |