Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Int J Biol Macromol. 2024 Jan;254(Pt 2):127925. doi: 10.1016/j.ijbiomac.2023.127925. Epub 2023 Nov 7.
Neuropathic pain (NP) is a prevalent medical condition that lacks an effective treatment. Recently, the Sigma-2 receptor (S2R) has been proposed as a potential therapeutic target for NP. Some highly-selective S2R ligands (UKH1114, CM398, and YTD) have shown promising results in vivo, but the molecular interaction between the S2R and these ligands has been scarcely investigated. This work explores changes in the S2R upon interaction with the three mentioned ligands using in silico approaches. The results indicated that the ICL1, H1, ICL2, and ECL are the most dynamic regions of S2R in all systems. Binding interaction analysis identified amino acids with significant contribution to the binding free energy. Notably, the UKH1114-S2R simulation trajectory revealed that small alterations in the ICL1, H1, ICL2, and ECL form a new stable opening in the S2R, linking the occluded S2R binding pocket to the endoplasmic reticulum lumen, providing more evidence for the assumptions about the EBP and S2R mechanism of function. Further, the agreement between the membrane parameters in our study and experimental values confirms the validity of the MD simulations. Overall, this study provides new insights into the interaction between anti-NP ligands and the S2R.
神经病理性疼痛（NP）是一种普遍存在的医学病症，目前缺乏有效的治疗方法。最近，Sigma-2 受体（S2R）被认为是治疗 NP 的潜在治疗靶点。一些高选择性的 S2R 配体（UKH1114、CM398 和 YTD）在体内显示出了有希望的结果，但 S2R 与这些配体之间的分子相互作用尚未得到充分研究。本工作使用计算方法探索了 S2R 在与三种提到的配体相互作用时的变化。结果表明，在所有系统中，ICL1、H1、ICL2 和 ECL 是 S2R 中最具动态性的区域。结合相互作用分析确定了对结合自由能有显著贡献的氨基酸。值得注意的是，UKH1114-S2R 模拟轨迹表明，ICL1、H1、ICL2 和 ECL 的微小变化形成了 S2R 中的一个新的稳定开口，将封闭的 S2R 结合口袋与内质网腔连接起来，为关于 EBP 和 S2R 功能机制的假设提供了更多证据。此外，我们研究中的膜参数与实验值之间的一致性证实了 MD 模拟的有效性。总的来说，这项研究提供了关于抗 NP 配体与 S2R 相互作用的新见解。
