Post‐translational modifications such as protein N‐glycosylation, significantly influence cellular processes. Dysregulated N‐glycosylation, exemplified in Grp94, a member of the Hsp90 family, leads to structural changes and the formation of epichaperomes, contributing to pathologies. Targeting N‐glycosylation‐induced conformations offers opportunities for developing selective chemical tools and drugs for these pathologic forms of chaperones. We here demonstrate how a specific Grp94 conformation induced by N‐glycosylation, identified previously via molecular dynamics simulations, rationalizes the distinct behavior of similar ligands. Integrating dynamic ligand unbinding information with SAR development, we differentiate ligands productively engaging the pathologic Grp94 conformers from those that are not. Additionally, analyzing binding site stereoelectronic properties and QSAR models using cytotoxicity data unveils relationships between chemical, conformational properties, and biological activities. These findings facilitate the design of ligands targeting specific Grp94 conformations induced by abnormal glycosylation, selectively disrupting pathogenic protein networks while sparing normal mechanisms.

中文翻译：

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N-糖基化诱导的病理蛋白构象作为指导选择生物活性小分子的工具


翻译后修饰（例如蛋白质 N-糖基化）显着影响细胞过程。 N-糖基化失调，例如 Hsp90 家族成员 Grp94，会导致结构变化和表层体形成，从而导致病理。针对 N-糖基化诱导的构象为开发针对这些病理形式的分子伴侣的选择性化学工具和药物提供了机会。我们在这里演示了先前通过分子动力学模拟识别的 N-糖基化诱导的特定 Grp94 构象如何合理化相似配体的独特行为。将动态配体解结合信息与 SAR 开发相结合，我们将有效地与病理性 Grp94 构象异构体结合的配体与那些不能有效结合的配体区分开来。此外，使用细胞毒性数据分析结合位点立体电子特性和 QSAR 模型揭示了化学、构象特性和生物活性之间的关系。这些发现有助于设计针对异常糖基化诱导的特定 Grp94 构象的配体，选择性破坏致病蛋白网络，同时不影响正常机制。