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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Palabras clave
Bond-based linear indices, Trypanosoma cruzi, Trypanosomicidal, Anti-epimastigote elimination, Amastigote susceptibility assay