Molecular Dynamics Studies on <i>Trypanosoma cruzi</i> Dihydroorotate Dehydrogenase Complexes: An Analysis of the Inhibitor Influence

Chagas disease remains a significant global health problem. Current etiological treatment is limited due to its low efficacy in the advanced stage of the disease and adverse effects. <i>Trypanosoma cruzi</i> dihydroorotate dehydrogenase (<i>Tc</i>DHODH) is a promising target for developing new drugs. This study explored the structural and dynamic factors influencing its inhibition. The results from the 100 ns molecular dynamics simulations of 11 ligand-<i>Tc</i>DHODH complexes revealed that ligand size and conformation play crucial roles in enzyme inhibition, with flexibility in the active site being essential for enzyme function. Small ligands tend to maintain a closed conformation, while larger ligands induce open conformations. The results further demonstrate ligand-induced conformational changes and the role of key hydrogen bonds in stabilizing the ligand-enzyme complex. Electrostatic and hydrophobic interactions between ligands and the enzyme's S1, S2, and S3 subsites contribute to inhibition. Understanding these factors facilitates the development of potent and selective <i>Tc</i>DHODH inhibitors for the treatment of Chagas disease.