JAC Advance Access published online on January 13, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki470
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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; Laboratoire de Parasitologie-Mycologie (EA3520), and Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010 Paris, France
* To whom correspondence should be addressed. 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.
Received June 16, 2005
Revised November 2, 2005
Accepted December 4, 2005
Original article
Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening
Nassira Mahmoudi 1,
Jesus-Vicente de Julián-Ortiz 2,
Liliane Ciceron 3,
Jorge Gálvez 4,
Dominique Mazier 3,
Martin Danis 3,
Francis Derouin 5,
and
Ramón García-Domenech 4 *
2 Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Dep. Química Física, Facultad de Farmacia, Universitat de València, Burjassot, Valencia, Spain; Xarxa de Recerca de Malalties Tropicals, Dep. Biología Celular y Parasitología, Facultat de Farmàcia. Universitat de València, Burjassot, Valencia, Spain
3 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
4 Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Dep. Química Física, Facultad de Farmacia, Universitat de València, Burjassot, Valencia, Spain
5 Laboratoire de Parasitologie-Mycologie (EA3520), and Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010 Paris, France
Ramón García-Domenech, E-mail: ramon.garcia{at}uv.es
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Mahmoudi, R. Garcia-Domenech, J. Galvez, K. Farhati, J.-F. Franetich, R. Sauerwein, L. Hannoun, F. Derouin, M. Danis, and D. Mazier New Active Drugs against Liver Stages of Plasmodium Predicted by Molecular Topology Antimicrob. Agents Chemother., April 1, 2008; 52(4): 1215 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sanchez, D. Thomas, E. J. Gillespie, R. Damoiseaux, J. Rogers, J. P. Saxe, J. Huang, M. Manchester, and K. A. Bradley Amiodarone and Bepridil Inhibit Anthrax Toxin Entry into Host Cells Antimicrob. Agents Chemother., July 1, 2007; 51(7): 2403 - 2411. [Abstract] [Full Text] [PDF]
|
|