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<p>Oxamniquine (OXA) exhibits selective efficacy against different <i>Schistosoma</i> species, with the highest activity observed in <i>Schistosoma mansoni</i> sulfotransferase (<i>Sm</i>SULT) and the lowest in <i>Schistosoma japonicum</i> sulfotransferase (<i>Sj</i>SULT). This study utilises advanced atomistic and molecular simulations to elucidate the structural dynamics induced by OXA binding to <i>Sm</i>SULT and <i>Sj</i>SULT, aiming to unravel the underpinnings of this selective efficacy. Binding free energy (BFE) analyses revealed a markedly higher affinity of OXA for <i>Sm</i>SULT (−48.04 kcal/mol) compared to wt<i>Sj</i>SULT (−22.84 kcal/mol), with a significant restoration of binding affinity (−39.23 kcal/mol) observed in <i>Sj</i>SULT following the mutation of Val139 to Gly139. Comprehensive conformational assessments highlighted that <i>Sm</i>SULT-OXA achieves its superior efficacy by stabilising the protein structure, in stark contrast to the erratic conformational behaviour of wild-type <i>Sj</i>SULT. Notably, this erratic behaviour is ameliorated upon mutation, leading to a restoration of OXA’s efficacy in <i>Sj</i>SULT. These insights elucidate the structural mechanisms underpinning OXA’s selective efficacy and provide valuable perspectives on its targeted action against <i>Schistosoma spp</i>.</p>

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Structural Mechanisms Driving the Selective Efficacy of Oxamniquine against Schistosoma mansoni and Schistosoma japonicum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月19日

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  • Kehinde F. Paul-Odeniran,
  • Emmanuel A. Iwuchukwu,
  • Paul O. Odeniran

摘要

Oxamniquine (OXA) exhibits selective efficacy against different Schistosoma species, with the highest activity observed in Schistosoma mansoni sulfotransferase (SmSULT) and the lowest in Schistosoma japonicum sulfotransferase (SjSULT). This study utilises advanced atomistic and molecular simulations to elucidate the structural dynamics induced by OXA binding to SmSULT and SjSULT, aiming to unravel the underpinnings of this selective efficacy. Binding free energy (BFE) analyses revealed a markedly higher affinity of OXA for SmSULT (−48.04 kcal/mol) compared to wtSjSULT (−22.84 kcal/mol), with a significant restoration of binding affinity (−39.23 kcal/mol) observed in SjSULT following the mutation of Val139 to Gly139. Comprehensive conformational assessments highlighted that SmSULT-OXA achieves its superior efficacy by stabilising the protein structure, in stark contrast to the erratic conformational behaviour of wild-type SjSULT. Notably, this erratic behaviour is ameliorated upon mutation, leading to a restoration of OXA’s efficacy in SjSULT. These insights elucidate the structural mechanisms underpinning OXA’s selective efficacy and provide valuable perspectives on its targeted action against Schistosoma spp.