Physicochemical properties of parent statins.

Schistosomiasis remains a global health challenge, affecting over 240 million people each year. Current treatment options, including praziquantel, are limited by their inability to target immature schistosomula and growing concerns around drug resistance. Targeting 3- hydroxy 3-methylglutaryl coenzyme A reductase from Schistosoma mansoni (SmHMGR), a key enzyme in the parasite’s mevalonate pathway, presents a promising therapeutic strategy. Although the antischistosomal potential of statins has been previously explored, this study introduces a novel integrated pipeline that combines homology modelling, large scale analogue screening of a 1013 compound chemical space, validated molecular docking, molecular dynamics simulations, and experimental validation to systematically identify SmHMGR inhibitors. Following computational prioritisation, experimental validation revealed modest activity of three commercially available statins (lovastatin, pravastatin, and pitavastatin) against schistosomula with up to 56.3% at 50 µM, but no significant time-dependent effects. Three novel analogues of pitavastatin exhibited enhanced schistosomicidal activity, revealing activities of up to 96% and 55% against schistosomula and adult worms at 50 µM, respectively. These findings highlight the potential of structural modifications to improve the efficacy of statin-based compounds against S. mansoni.