Fragment Screening Reveals Novel Scaffolds against Sirtuin-2-Related Protein 1 from <i>Trypanosoma brucei</i>
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 <i>Trypanosoma brucei</i> 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 IC<sub>50</sub> value of 17.8 μM 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.
Authors
- Marcelo D. Polêto (ORCID: https://orcid.org/0000-0001-9210-690X)
- Sandro R. Marana (ORCID: https://orcid.org/0000-0002-5117-1921)
- Andreas Bender (ORCID: https://orcid.org/0000-0002-6683-7546)
- Flávio da Silva Emery (ORCID: https://orcid.org/0000-0002-8652-7123)
- Veridiana de Melo Rodrigues (ORCID: https://orcid.org/0000-0002-3386-9197)
- Renan Augusto Gomes
- Gustavo Henrique Goulart Trossini (ORCID: https://orcid.org/0000-0003-3634-2531)
- Vitor M. Almeida (ORCID: https://orcid.org/0000-0003-4972-3341)
- Hugo Verli (ORCID: https://orcid.org/0000-0002-4796-8620)
- Bruna Fleck Godoi (ORCID: https://orcid.org/0000-0002-5910-0511)
Institutions
- Universidade Federal do Rio Grande do Sul (BR)
- Universidade de São Paulo (BR)
- University of Cambridge (GB)
- Centre of Excellence in Molecular Biology (PK)
Publication Details
- Journal
- ACS Omega
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1021/acsomega.4c09231
- Citations
- 1
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 0.34
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade Federal do Rio Grande do Sul
- Universidade de São Paulo