Elucidating the binding mechanisms of compounds targeting glutathione S-transferase for schistosomiasis therapy using molecular docking, clustering-based analysis and molecular dynamics studies

Abstract

Schistosoma japonicum causes zoonotic schistosomiasis, which remains a public health concern in endemic regions and underscores the need for novel antischistosomal agents with well-defined molecular targets. This study evaluated bioactive compounds from Bischofia javanica for their interactions with glutathione S-transferase (GST) using molecular docking, clustering-based binding analysis, and molecular dynamics simulations. The predicted binding modes were evaluated in relation to two structurally relevant ligand-recognition regions corresponding to the canonical glutathione-binding site and the Praziquantel-associated allosteric region at the dimer interface. Integration of ligand affinity, binding stability, and residue-level interaction patterns across these regions identified Epifriedelanyl acetate and Friedelin as the leading compounds. Epifriedelanyl acetate exhibited the strongest overall binding profile and more favorable binding energetics than praziquantel. Its interactions were predominantly concentrated within the allosteric region with limited extension toward the catalytic-proximal environment. Friedelin also exhibited favorable and stable binding forming a compact interaction network within the same praziquantel-associated region, although its binding energetics were slightly less favorable than those of the control. Per-residue energy decomposition and native contact occupancy confirmed persistent interactions within the allosteric region whereas principal component analysis revealed broader conformational redistribution for Epifriedelanyl acetate and a more localized response for Friedelin without disrupting the global GST fold. Overall, these findings support Epifriedelanyl acetate and Friedelin as promising GST-targeting antischistosomal candidates that may modulate GST predominantly through an allosteric mechanism.

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