Title:Molecular Features for Antitrypanosomal Activity of Thiosemicarbazones Revealed by OPS-PLS QSAR Studies
Volume: 8
Issue: 6
Author(s): Norka Beatriz Huaman Lozano, Vinicius Goncalves Maltarollo, Karen Cacilda Weber, Kathia Maria Honorio, Rafael Victorio Carvalho Guido, Adriano Defini Andricopulo and Alberico Borges Ferreira Da Silva
Affiliation:
Keywords:
Chagas' disease, Cysteine protease cruzain, Thiosemicarbazones, Molecular modeling, Quantum chemical methods,
DFT, OPS-PLS studies, Drug design
Abstract: A quantitative structure–activity relationship analysis was employed to explore the relationship between the
molecular structure of thiosemicarbazone analogues and the inhibition of the cysteine protease cruzain, a validated target
for Chagas’ disease treatment. A data set containing 53 thiosemicarbazone derivatives was used to produce a quantitative
model for activity prediction of unknown compounds. Several electronic descriptors were obtained through DFT calculations,
along with a large amount of Dragon descriptors. The ordered predictor selection (OPS) algorithm was employed to
select the most relevant descriptors to perform PLS regressions. With this procedure, significant correlation coefficients
(r
2 = 0.85, q
2 = 0.78) were achieved. Furthermore, predicted values for an external test set are in good agreement with the
experimental results, indicating the potential of the model for untested compounds. Additional validation tests were carried
out, indicating that a robust and reliable model was obtained to be used in the design of new thiosemicarbazones with
improved cruzain inhibition potential.
