Application of linear discriminant analysis in the virtual screening of antichagasic drugs through trypanothione reductase inhibition

JULIÁN J. PRIETO; ALAN TALEVI; LUIS E. BRUNO-BLANCH

MOLECULAR DIVERSITY

Springer

Año: 2006 vol. 10 p. 361 - 375

We have performed virtual screening to identify new lead trypanothione reductase inhibitor (TRI) compounds, enzyme present in Tripanozoma cruzi, the agent responsible of Chagas disease. From a training set of 58 compounds, linear discriminant analysis (LDA) was performed using 2D and 3D descriptors as discriminating variables in order to find out which function of descriptors characterizes the active TRI. The values of the statistical parameters F - Snedecor and Wilk´s ë for the discriminant function (DF) showed good statistical significance, as long as the rate of success in the prediction for both the training and the test set: 91.38% and 88.63%, in that order. Internal validation through the Leave ? Group ? Out methodology was performed with good results, assuring the stability of the DF. Afterwards, the DF was applied in virtual screening of 422,367 compounds. The optimum range of values of octanol ? water partition coefficient for a compound to develop trypanothione reductase inhibition was applied as a second filtering criteria. 739 structurally heterogeneous drugs of the virtual library were selected as promissory TRI.