Rafaela Molina de Angelo, Michell O. Almeida, João Pedro P. Encide, Henrique Barbosa, Daniel da Silva Sousa, Aldineia Pereira da Silva, Marina Sena Mendes, Maria Cristina Nonato, Albérico Borges Ferreira da Silva, João Henrique Ghilardi Lago, Káthia M. Honório
Abstract Schistosomiasis is a parasitic disease affecting millions worldwide, highlighting the urgent need for effective treatments. This study investigated a new potential site on Schistosoma mansoni dihydroorotate dehydrogenase ( Sm DHODH) and identified natural compounds as inhibitors from in silico and experimental techniques. Molecular docking and dynamics simulations revealed significant interactions between Sm DHODH and ent -kaur-16-en-19-oic acid (3) and 15β-senecioil-oxi-ent-kaur-16-en-19-oic acid (4). The complex formed by compound 3 and the biological target showed the lowest free binding energy, indicating greater stability. Experimental assays indicated that compound 3 significantly reduced Sm DHODH activity (40 ± 2% at 250 µM), while compound 4 had minimal effect (90 ± 1%). Structural analyses revealed that hydrophobic interactions at site 1 and conformational changes induced by compound 3 are crucial for effective enzyme inhibition. Therefore, from the computational and experimental approaches employed in this study, we were able to understand a possible mechanism related to the Sm DHODH inhibition and the discovery of a potential bioactive compound against this important target related to schistosomiasis.