Discovery of novel dihydroorotate dehydrogenase inhibitors in trypanosomatids through a molecular docking and molecular dynamics approach

Abstract

The classical treatments for the diseases caused by trypanosomatids are associated to severe side effects, including death. Furthermore, drug resistant parasites are a major health problem in different endemic countries. For those reasons, there is an urgent need for new, safe and inexpensive anti-trypanosomatid drugs. One strategy is through the structure-based design of inhibitors against essential molecular targets. Our study focuses in one enzyme, the dihydroorotate dehydrogenase from Leishmania major and Trypanosoma cruzi. Both parasite’s protein crystals were used to find novel active compounds through a virtual screening approach, combining a molecular docking analysis followed by a refinement stage of the binding score based on molecular dynamics simulations. An initial set of ~600.000 compounds were tested, obtaining at the end 16 promising molecules ranked by the predicted binding energies and the interactions created after visual inspection. The refinement protocol prioritized the molecules for further validation using in vitro experiments.