Ligand-based discovery of novel trypanosomicidal drug-like compounds: In silico identification and experimental support

Fecha

2011

Autores

Castillo Garit, Juan Alberto
Vega, Maria Celeste
Rolón, Miriam
Marrero Ponce, Yovani
Gómez Barrio, Alicia
Escario, José A.
Alvarez Bello, Alfredo
Montero Torres, Alina
Torrens, Francisco
Pérez Giménez, Facundo

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Resumen

Two-dimensional bond-based linear indices and linear discriminant analysis are used in this report to perform a quantitative structureeactivity 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 mg/mL. Besides, three compounds show more than 70% of AE at a concentration of 10 mg/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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Bond-based linear indices, Trypanosoma cruzi, Trypanosomicidal, Anti-epimastigote elimination, Amastigote susceptibility assay

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