Molecular docking and quantitative structure-activity relationships for a series of Trypanosoma cruzi dihydroorotate dehydrogenase inhibitors

Abstract

Abstract Caused by the protozoan Trypanosoma cruzi, Chagas disease affects six to seven million people worldwide, mainly in Latin America. The drugs currently available for treating the disease are ineffective during its chronic phase and have serious adverse effects. Essential for the survival of T. cruzi, the enzyme dihydroorotate dehydrogenase (DHODH) has become a key molecular target for drug discovery in Chagas disease. This study investigates the bi-dimensional and three-dimensional quantitative structure-activity relationships (QSAR) for a series of 64 T. cruzi DHODH inhibitors. The results indicate a highly predictive 2D Hologram QSAR (HQSAR) model (q 2 = 0.65, r 2 = 0.88, and r 2 pred = 0.82) that identified key molecular fragments that correlate with DHODH inhibition. Moreover, 3D Comparative Molecular Field Analysis (CoMFA) models (q 2 = 0.75, r 2 = 0.99, and r 2 pred = 0.66) pointed out the 3D molecular features that determine the activity of the inhibitors. Although restricted to a congeneric series and focused solely on 2D and 3D descriptors, these QSAR models and molecular docking analyses identified key properties and intermolecular interactions for designing and optimizing new compounds as potent T. cruzi DHODH inhibitors.

Keywords

• Trypanosoma cruzi
• Medicinal chemistry
• QSAR
• Dihydroorotate dehydrogenase
• Inhibitors
• Chagas disease