title: Discovery of new inhibitors of Schistosoma mansoni PNP by pharmacophore-based virtual screening.
abstract: Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma mansoni , one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure-activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 μM. The most potent inhibitors 7, 10, and 17 with IC(50) of 2, 18, and 38 μM, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.
authors.affiliation: Laboratório de Química Medicinal e Computacional, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP, Brazil.
authors.forename: Matheus P
authors.initials: MP
authors.lastname: Postigo
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.forename: Glaucius
authors.initials: G
authors.lastname: Oliva
authors.forename: Marcelo S
authors.initials: MS
authors.lastname: Castilho
authors.forename: Ivan
authors.initials: I
authors.lastname: da R Pitta
authors.forename: Julianna F C
authors.initials: JF
authors.lastname: de Albuquerque
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012550:Schistosoma mansoni / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase