title: Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening.
abstract: Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization.
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás , Rua 240, Qd.87, Setor Leste Universitário, Goiânia 74605-510, Brazil.
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Neves
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Dantas
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Senger
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás , Rua 240, Qd.87, Setor Leste Universitário, Goiânia 74605-510, Brazil.
authors.forename: Cleber C
authors.initials: CC
authors.lastname: Melo-Filho
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Walter C G
authors.initials: WC
authors.lastname: Valente
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Ana C M
authors.initials: AC
authors.lastname: de Almeida
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: João M
authors.initials: JM
authors.lastname: Rezende-Neto
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Elid F C
authors.initials: EF
authors.lastname: Lima
authors.affiliation: Department of Infection and Immunity, London School of Hygiene and Tropical Medicine , London WC1E 7HT, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Paveley
authors.affiliation: 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: Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill North Carolina 27955-7568, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Muratov
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: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás , Rua 240, Qd.87, Setor Leste Universitário, Goiânia 74605-510, Brazil.
authors.forename: Rodolpho C
authors.initials: RC
authors.lastname: Braga
authors.affiliation: LaBECFar-Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz , Fundação Oswaldo Cruz, Av. Brasil, 4365, Rio de Janeiro 21040-900, Rio de Janeiro, Brazil.
authors.forename: Floriano P
authors.initials: FP
authors.lastname: Silva-Junior
authors.affiliation: LabMol-Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás , Rua 240, Qd.87, Setor Leste Universitário, Goiânia 74605-510, Brazil.
authors.forename: Carolina Horta
authors.initials: CH
authors.lastname: Andrade
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012550:Schistosoma mansoni / Q000187:drug effects*; D012552:Schistosomiasis / Q000188:drug therapy*; D012556:Schistosomicides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D012556:Schistosomicides