Journal Article

Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening

Nassira Mahmoudi, Jesus-Vicente de Julián-Ortiz, Liliane Ciceron, Jorge Gálvez, Dominique Mazier, Martin Danis, Francis Derouin and Ramón García-Domenech

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 57, issue 3, pages 489-497
Published in print March 2006 | ISSN: 0305-7453
Published online January 2006 | e-ISSN: 1460-2091 | DOI:
Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening

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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

Journal Article.  5299 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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