Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, 195251 St. Petersburg, Russia.
Laboratory of Structural Bioinformatics, Institute of Biomedicine and Pharmacy, Russian-Armenian University, Yerevan 0051, Armenia.
Int J Mol Sci. 2021 Dec 19;22(24):13618. doi: 10.3390/ijms222413618.
Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer's disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.
钙库操纵性钙内流（SOCE）构成了一种精细调节机制，负责细胞内储存的补充。海马体 SOCE 由三部分组成的复合物 TRPC6/ORAI2/STIM2 中的钙库操纵性通道（SOC）调节。有研究表明，在神经元中，SOCE 在静息状态下维持细胞内钙稳态，并需要支持树突棘的结构。最近的证据表明，SOC 的正调节剂是治疗早期阿尔茨海默病（AD）的潜在药物候选物。尽管 STIM2 和 ORAI2 肯定参与了 nSOC 幅度的调节，并在 AD 发病机制中发挥了主要作用，但越来越多的证据表明，通过药理学靶向这些蛋白质并不容易。现有的 TRPC6 正调节剂由于药代动力学差或副作用而不适合药物开发。因此，我们集中讨论了基于 TRPC6、ORAI2 和 STIM2 的现有 3D 结构开发特定 nSOC 调节剂的前景。我们简要描述了现有模型的结构特征以及制备它们所使用的方法。我们提供了基于靶蛋白 3D 结构常用的药物设计步骤，这些步骤可能用于开发新的 AD 预防疗法。
