Fragment Screening Reveals Novel Scaffolds against Sirtuin-2-Related Protein 1 from Trypanosoma brucei

Author(s)

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.

• Document type: Journal article
• Source: ACS OMEGA; v. 10, n. 4, p. 12-pg., 2024-12-27.

Abstract

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)

• FAPESP's process: 23/07081-8 - Hit to lead optimization of heterocycles containing isoindolones as antitrypanosomal agents
• Grantee: Bruna Fleck Godoi
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/25543-8 - Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors
• Grantee: Gustavo Henrique Goulart Trossini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/50677-7 - Exploring epigenetic targets to fight neglected diseases: Selective sirtuin-2 inhibitors as leishmanicidal compounds
• Grantee: Flavio da Silva Emery
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE