Molecular Dynamics Studies on 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. dihydroorotate dehydrogenase (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-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 DHODH inhibitors for the treatment of Chagas disease.