JAC Advance Access originally published online on January 13, 2006
Journal of Antimicrobial Chemotherapy 2006 57(3):489-497; doi:10.1093/jac/dki470
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Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening
1 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; 2 Laboratoire de Parasitologie-Mycologie (EA3520), and Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010 Paris, France; 3 Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Dep. Química Física, Facultad de Farmacia, Universitat de València, Burjassot, Valencia, Spain; 4 Xarxa de Recerca de Malalties Tropicals, Dep. Biología Celular y Parasitología, Facultat de Farmàcia. Universitat de València, Burjassot, Valencia, Spain
Received 16 June 2005; returned 16 October 2005; revised 2 November 2005; accepted 4 December 2005
* Corresponding author. Tel: +34-63544291; Fax: +34-63544892; E-mail: ramon.garcia{at}uv.es
Objectives: 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 µM 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.
Keywords: molecular topology , topological indices , antimalarials , Plasmodium falciparum , QSAR studies
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