Exploring SmDHODH inhibition: natural products with potential anti-schistosomiasis activity

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.