Abstract：
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.
摘要：
神经性疼痛(NP)是缺乏有效治疗的普遍医学病症。最近,Sigma-2受体(S2R)已被提出作为NP的潜在治疗靶标。一些高选择性S2R配体（UKH1114，CM398和YTD）在体内显示出有希望的结果，但是几乎没有研究S2R与这些配体之间的分子相互作用。这项工作探索了使用计算机模拟方法与三种上述配体相互作用时S2R的变化。结果表明，ICL1，H1，ICL2和ECL是所有系统中S2R最动态的区域。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模拟轨迹显示，ICL1、H1、ICL2和ECL的微小变化在S2R中形成了一个新的稳定开口，将闭塞的S2R结合袋连接到内质网腔，为有关EBP和S2R功能机制的假设提供了更多证据。Further,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,这项研究为抗NP配体与S2R之间的相互作用提供了新的见解。
