title: Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening.
abstract: OBJECTIVE
  A quantitative structure-activity relationship study using a database of 395 compounds previously tested against chloroquine-susceptible strains of the blood stages of Plasmodium falciparum to predict new in vitro antimalarial drugs has been developed.
  
  
  METHODS
  Topological indices were used as structural descriptors and were related to antimalarial activity by using linear discriminant analysis (LDA) and multilinear regression (MLR). Two discriminant equations were obtained (FD1 and FD2), which allowed us to carry out successful classification of 90% and 80% of compounds, respectively. The IC50 values of the compounds were introduced to get an MLR equation model suitable to predict their in vitro activities.
  
  
  RESULTS
  Using this model, a set of 27 drugs against a chloroquine-susceptible clone (3D7) of P. falciparum have been selected and evaluated in vitro. Among these drugs are monensin, nigericin, vincristine, vindesine, ethylhydrocupreine and salinomycin with in vitro IC50s at nanomolar concentrations (0.3, 0.4, 2, 6, 26 and 188 nM, respectively). Other compounds such as hycanthone, amsacrine, aphidicolin, bepridil, amiodarone, ranolazine and triclocarban showed in vitro IC50 values below 5 microM in the mathematical model.
  
  
  CONCLUSIONS
  These results demonstrate the usefulness of the approach for the selection and design of new lead drugs active against P. falciparum.
authors.affiliation: INSERM U511, Immuno-biologie Cellulaire et Moléculaire des Infections Parasitaires, CHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Nassira
authors.initials: N
authors.lastname: Mahmoudi
authors.forename: Jesus-Vicente
authors.initials: JV
authors.lastname: de Julián-Ortiz
authors.forename: Liliane
authors.initials: L
authors.lastname: Ciceron
authors.forename: Jorge
authors.initials: J
authors.lastname: Gálvez
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Martin
authors.initials: M
authors.lastname: Danis
authors.forename: Francis
authors.initials: F
authors.lastname: Derouin
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Domenech
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D016002:Discriminant Analysis; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020128:Inhibitory Concentration 50; D016014:Linear Models; D008954:Models, Biological; D015394:Molecular Structure; D015999:Multivariate Analysis; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials