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<p>Trypanosomatids are etiological agents of diseases such as Leishmaniasis, Chagas disease, and Human African trypanosomiasis, and their treatments face challenges such as toxicity, patient compliance, drug resistance, and underfunded drug development. As a primary mechanism of parasite defense against oxidative stress, superoxide dismutase enzymes (SODs) are putative drug targets for efforts to develop drugs to fight diseases caused by trypanosomatids. However, the small volume of SODs’ active sites renders them undruggable by rule-of-5 compliant compounds. To circumvent this limitation, extensive in silico studies were performed to identify druggable putative allosteric pockets in SODs from trypanosomatids that are absent in human SODs. Crystallographic structures of SODs (human, <i>Trypanosoma,</i> and Leishmania) were clustered using a principal component analysis of their coordinates, as available on the Bio3D R package. Then, the highest-resolution representative of each cluster (the most dissimilar conformational state) was submitted to computational solvent mapping on the FTMove server. The consensus sites identified by this approach were analyzed on the DRUGpy plugin to identify putative druggable and borderline-druggable hotspots and compare their properties. The residues surrounding these hotspots were also investigated using the PocketMatch server, and their correlation with the active site was further evaluated through molecular dynamics. Despite their different evolutionary origins, Human MnSOD (SOD2) and trypanosomatid FeSOD have putative allosteric binding sites predicted at equivalent locations, implying that isoforms should be considered when evaluating new allosteric modulators targeting parasite SODs.</p>

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Identification and characterization of putative allosteric sites on superoxide dismutases for use as species-specific drug targets to parasitic trypanosomatids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Bruno C. Souza,
  • Thamires Q. Froes,
  • Marcelo S. Castilho,
  • Franco H. A. Leite

摘要

Trypanosomatids are etiological agents of diseases such as Leishmaniasis, Chagas disease, and Human African trypanosomiasis, and their treatments face challenges such as toxicity, patient compliance, drug resistance, and underfunded drug development. As a primary mechanism of parasite defense against oxidative stress, superoxide dismutase enzymes (SODs) are putative drug targets for efforts to develop drugs to fight diseases caused by trypanosomatids. However, the small volume of SODs’ active sites renders them undruggable by rule-of-5 compliant compounds. To circumvent this limitation, extensive in silico studies were performed to identify druggable putative allosteric pockets in SODs from trypanosomatids that are absent in human SODs. Crystallographic structures of SODs (human, Trypanosoma, and Leishmania) were clustered using a principal component analysis of their coordinates, as available on the Bio3D R package. Then, the highest-resolution representative of each cluster (the most dissimilar conformational state) was submitted to computational solvent mapping on the FTMove server. The consensus sites identified by this approach were analyzed on the DRUGpy plugin to identify putative druggable and borderline-druggable hotspots and compare their properties. The residues surrounding these hotspots were also investigated using the PocketMatch server, and their correlation with the active site was further evaluated through molecular dynamics. Despite their different evolutionary origins, Human MnSOD (SOD2) and trypanosomatid FeSOD have putative allosteric binding sites predicted at equivalent locations, implying that isoforms should be considered when evaluating new allosteric modulators targeting parasite SODs.