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

IF 1.8 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Biochemistry and Biophysics Pub Date : 2025-04-19 DOI:10.1007/s12013-025-01756-9

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

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引用次数: 0

Abstract

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.

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奥氨喹对曼氏血吸虫和日本血吸虫选择性作用的结构机制研究。

Oxamniquine （OXA）对不同种类血吸虫具有选择性抑制作用，其中对曼氏血吸虫（Schistosoma mansoni）硫转移酶（SmSULT）活性最高，对日本血吸虫（Schistosoma japonicum）硫转移酶活性最低。本研究利用先进的原子和分子模拟来阐明OXA与SmSULT和SjSULT结合诱导的结构动力学，旨在揭示这种选择性效果的基础。结合自由能（BFE）分析显示，OXA对SmSULT的亲和力（-48.04 kcal/mol）明显高于wtSjSULT (-22.84 kcal/mol)，在Val139突变为Gly139后，SjSULT的结合亲和力显著恢复（-39.23 kcal/mol）。综合构象评估强调，SmSULT-OXA通过稳定蛋白质结构来实现其优越的疗效，与野生型SjSULT的不稳定构象行为形成鲜明对比。值得注意的是，这种不稳定的行为在突变后得到改善，导致OXA在SjSULT中的疗效恢复。这些发现阐明了OXA选择性作用的结构机制，并为OXA抗血吸虫的靶向作用提供了有价值的视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Biochemistry and Biophysics 生物-生化与分子生物学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

7.5 months

期刊介绍： Cell Biochemistry and Biophysics (CBB) aims to publish papers on the nature of the biochemical and biophysical mechanisms underlying the structure, control and function of cellular systems The reports should be within the framework of modern biochemistry and chemistry, biophysics and cell physiology, physics and engineering, molecular and structural biology. The relationship between molecular structure and function under investigation is emphasized. Examples of subject areas that CBB publishes are: · biochemical and biophysical aspects of cell structure and function; · interactions of cells and their molecular/macromolecular constituents; · innovative developments in genetic and biomolecular engineering; · computer-based analysis of tissues, cells, cell networks, organelles, and molecular/macromolecular assemblies; · photometric, spectroscopic, microscopic, mechanical, and electrical methodologies/techniques in analytical cytology, cytometry and innovative instrument design For articles that focus on computational aspects, authors should be clear about which docking and molecular dynamics algorithms or software packages are being used as well as details on the system parameterization, simulations conditions etc. In addition, docking calculations (virtual screening, QSAR, etc.) should be validated either by experimental studies or one or more reliable theoretical cross-validation methods.