9Th Brazilian Symposium on Medicinal Chemistry

Endemic in Latin America, Chagas disease affects 8 million people worldwide and is caused by the protozoan Trypanosoma cruzi.1 The trypanosomatid enzyme dihydroorotate dehydrogenase (TcDHODH) catalyzes the oxidation of (S)-dihydroorotate to orotate, a key reaction in the pyrimidine biosynthesis pathway.2 In this study, 3D quantitative structure-activity relationship models for a series of TcDHODH inhibitors were built using Comparative Molecular Field Analysis (CoMFA).3 The data set features 64 TcDHODH inhibitors collected from the literature (enzyme-inhibitor dissociation constants, Ki values, from 24 nM to 7.78 µM).4 The most robust CoMFA model showed high internal (q2 = 0.75 and r2 = 0.99) and external (r2pred = 0.66) statistical consistency. Moreover, the CoMFA contour maps highlighted the most relevant molecular features that influence the activity of the inhibitors. These results can be used as guidelines for the design of optimized TcDHODH inhibitors within the structural landscape of the investigated data set.