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

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 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.