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  • Title: Ligand-based discovery of novel trypanosomicidal drug-like compounds: in silico identification and experimental support.
    Author: Castillo-Garit JA, Vega MC, Rolón M, Marrero-Ponce Y, Gómez-Barrio A, Escario JA, Bello AA, Montero A, Torrens F, Pérez-Giménez F, Arán VJ, Abad C.
    Journal: Eur J Med Chem; 2011 Aug; 46(8):3324-30. PubMed ID: 21605926.
    Abstract:
    Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A database with 143 anti-trypanosomal and 297 compounds having other clinical uses, are utilized to develop the theoretical models. The best discriminant models computed using bond-based linear indices provides accuracies greater than 90 for both training and test sets. Our models identify as anti-trypanosomals five out of nine compounds of a set of already-synthesized substances. The in vitro anti-trypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a perfect agreement between theoretical predictions and experimental results. The compounds identified as active ones show more than 98% of anti-epimastigote elimination (AE) at a concentration of 100 μg/mL. Besides, three compounds show more than 70% of AE at a concentration of 10 μg/mL. Finally, compounds with the best "activity against epimastigote forms/unspecific cytotoxicity" ratio are evaluated using an amastigote susceptibility assay. It should be noticed that, compound Va7-71 exhibit a 100% of intracellular amastigote elimination and shows similar activity when compared to a standard trypanosomicidal as nifurtimox. Finally, we can emphasize that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new anti-trypanosomal compounds.
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