title: QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.
abstract: Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents.
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias , Rua 240, Qd.87, Goiania, GO 74605-510, Brazil.
authors.forename: Cleber C
authors.initials: CC
authors.lastname: Melo-Filho
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Dantas
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias , Rua 240, Qd.87, Goiania, GO 74605-510, Brazil.
authors.forename: Rodolpho C
authors.initials: RC
authors.lastname: Braga
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias , Rua 240, Qd.87, Goiania, GO 74605-510, Brazil.
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Neves
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Senger
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Walter C G
authors.initials: WC
authors.lastname: Valente
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: João M
authors.initials: JM
authors.lastname: Rezende-Neto
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Willian T
authors.initials: WT
authors.lastname: Chaves
authors.affiliation: Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.|Department of Chemical Technology, Odessa National Polytechnic University , 1. Shevchenko Ave., Odessa, 65000, Ukraine.
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Muratov
authors.affiliation: Department of Pathogen Molecular Biology & Department of Infection and Immunity, London School of Hygiene and Tropical Medicine , London WC1E 7HT, United Kingdom.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Paveley
authors.affiliation: Department of Pathogen Molecular Biology & Department of Infection and Immunity, London School of Hygiene and Tropical Medicine , London WC1E 7HT, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Furnham
authors.affiliation: Imaging Platform, Broad Institute of Massachusetts Institute of Technology and Harvard , Cambridge, Massachusetts 02142, United States.
authors.forename: Lee
authors.initials: L
authors.lastname: Kamentsky
authors.affiliation: Imaging Platform, Broad Institute of Massachusetts Institute of Technology and Harvard , Cambridge, Massachusetts 02142, United States.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.affiliation: Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute , Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Floriano P
authors.initials: FP
authors.lastname: Silva-Junior
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias , Rua 240, Qd.87, Goiania, GO 74605-510, Brazil.
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000871:Anthelmintics; D009097:Multienzyme Complexes; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase