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

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 (SmDHODH) and identified natural compounds as inhibitors from in silico and experimental techniques. Molecular docking and dynamics simulations revealed significant interactions between SmDHODH 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 SmDHODH 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 SmDHODH inhibition and the discovery of a potential bioactive compound against this important target related to schistosomiasis.

The online version contains supplementary material available at 10.1007/s40203-026-00628-1.