| Texto completo | |
| Autor(es): |
Gomes, Renan A.
;
Poleto, Marcelo D.
;
Verli, Hugo
;
Almeida, Vitor M.
;
Marana, Sandro R.
;
Bender, Andreas
;
Godoi, Bruna F.
;
Rodrigues, Vinicius T. L.
;
Emery, Flavio de S.
;
Trossini, Gustavo H. G.
Número total de Autores: 10
|
| Tipo de documento: | Artigo Científico |
| Fonte: | ACS OMEGA; v. 10, n. 4, p. 12-pg., 2024-12-27. |
| Resumo | |
Sirtuin-2 (Sir2) is a histone deacetylase recognized as an antitrypanosomal target, yet there is limited knowledge regarding their potent inhibitors. This investigation employs the fragment-based drug discovery (FBDD) framework to identify novel inhibitors against Trypanosoma brucei Sir2-related protein 1. Initially, frequent residue-ligand interactions extracted from the crystallographic structures of human Sir2 and key features of human and parasitic Sir2 active sites were utilized to curate a targeted fragment library. Screening identified ten fragment hits, which introduced nine novel substructures compared to known Sir2 inhibitors. Among these, fragment 1 was the most potent, with an IC50 value of 17.8 mu M and a ligand efficiency of 0.41. Further chemical space exploration of 30 compounds from the two most promising hits confirmed fragment 1 as the most potent. This study underscores the effectiveness of FBDD in discovering chemically distinct starting points with favorable ligand efficiency against protein targets in infectious diseases. (AU) | |
| Processo FAPESP: | 23/07081-8 - Otimização hit to lead de heterociclos baseados em isoindolonas como agentes contra Tripanossomíase |
| Beneficiário: | Bruna Fleck Godoi |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 17/25543-8 - Estratégias de Química Medicinal (LBDD e SBDD) na busca de inibidores de Sirtuína 2 de tripanossomatídeos |
| Beneficiário: | Gustavo Henrique Goulart Trossini |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 13/50677-7 - Explorando alvos epigenéticos contra doenças negligenciadas: inibidores seletivos de sirtuina-2 como agentes leishmanicidas |
| Beneficiário: | Flavio da Silva Emery |
| Modalidade de apoio: | Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE |