Fragment Screening\nReveals Novel Scaffolds against\nSirtuin-2-Related Protein 1 from Trypanosoma brucei

Sirtuin-2 (Sir2) is a histone deacetylase recognized\nas an antitrypanosomal\ntarget, yet there is limited knowledge regarding their potent inhibitors.\nThis investigation employs the fragment-based drug discovery (FBDD)\nframework to identify novel inhibitors against Trypanosoma\nbrucei Sir2-related protein 1. Initially, frequent\nresidue–ligand interactions extracted from the crystallographic\nstructures of human Sir2 and key features of human and parasitic Sir2\nactive sites were utilized to curate a targeted fragment library.\nScreening identified ten fragment hits, which introduced nine novel\nsubstructures compared to known Sir2 inhibitors. Among these, fragment\n1 was the most potent, with an IC<sub>50</sub> value of 17.8 μM\nand a ligand efficiency of 0.41. Further chemical space exploration\nof 30 compounds from the two most promising hits confirmed fragment\n1 as the most potent. This study underscores the effectiveness of\nFBDD in discovering chemically distinct starting points with favorable\nligand efficiency against protein targets in infectious diseases.