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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 <jats:italic><jats:italic>Schistosoma mansoni<\/jats:italic><\/jats:italic> (<jats:italic><jats:italic>Sm<\/jats:italic><\/jats:italic>HMGR), a key enzyme in the parasite\u2019s 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 10<jats:sup>13<\/jats:sup> compound chemical space, validated molecular docking, molecular dynamics simulations, and experimental validation to systematically identify <jats:italic><jats:italic>Sm<\/jats:italic><\/jats:italic>HMGR 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 \u00b5M, 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 \u00b5M, respectively. 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