Inhibitors of Serine Acetyltransferase Induce Lethality in Entamoeba histolytica and Leishmania donovani.

The limited efficacy and emerging resistance to current antiamoebic agents highlight the urgent need for new therapies. Serine acetyltransferase isoform 3, essential for cysteine biosynthesis in Entamoeba histolytica, plays a crucial role in cellular survival and pathogenicity, making it a promising drug target. We performed structure-guided virtual screening of 1.35 million compounds using ligand-based pharmacophore modeling and molecular docking, identifying ten top inhibitors with distinct binding poses in the enzyme's elongated active site. Group I and II compounds occupied both the serine- and CoA-binding pockets and showed potent inhibition (IC50: 9-18 μM). Group III compounds, binding only the serine site, showed modest activity, while Group IV compounds exhibited strong enzymatic and cellular inhibition despite similar binding, indicating effective single-site targeting. Molecular dynamics confirmed binding stability. Eight compounds inhibited E. histolytica growth, with four fully suppressing parasite growth. Notably, Group IV compound F0473-0289 also targeted Leishmania donovani with minimal mammalian THP-1 cell toxicity, highlighting its potential as a selective and safe antiparasitic lead.