Department of Drug Sciences , University of Pavia , Viale Taramelli 12 , 27100 Pavia , Italy.
Center for Bioinformatics and Molecular Simulation , Universidad de Talca , 1 Poniente , 1141 Talca , Chile.
J Chem Inf Model. 2020 Feb 24;60(2):756-765. doi: 10.1021/acs.jcim.9b00649. Epub 2019 Dec 20.
Significant progresses have been made to understand the molecular basis of the Sigma1 receptor (S1R) operating in normal and pathological conditions. S1R is a transmembrane protein that participates in a wide variety of processes at the central nervous system; hence, its function has been associated with mental and neurological disorders. Several ligands have been proposed to regulate the function of S1R revealing a high plasticity of the ligand-binding pocket. Previous drug-design studies have been mainly based on pharmacophore models; however, the recently revealed crystal structure of S1R provides an excellent opportunity for verifying previous predictions and for evaluating the binding of novel compounds. Interestingly, the crystal structure shows that the binding pocket of S1R is highly occluded from solvent; therefore, it is not clear how ligands access this site. In the present work, we applied steered molecular dynamics (SMD) simulations to open the occluded ligand-binding pocket in the S1R crystal structure and to determine the preferred ligand pathway to enter and exit the binding site. The intracellular surface of the β-barrel ligand-binding region was found the most favorable route to accommodate ligands. This route supports the binding of RC-33 (our in-house-developed S1R modulator) and a new bivalent derivative that constitutes the first divalent structure shown to interact with S1R. Free energy calculations of these compounds associated with S1R agree with experimental values and provide molecular insights of the binding mode of modulators that could access the S1R ligand-binding pocket through the cytoplasmic region.
在理解西格玛 1 型受体（S1R）在正常和病理条件下的分子基础方面已经取得了重大进展。S1R 是一种跨膜蛋白，它参与中枢神经系统的多种过程；因此，其功能与精神和神经紊乱有关。已经提出了几种配体来调节 S1R 的功能，揭示了配体结合口袋的高度可塑性。以前的药物设计研究主要基于药效基团模型；然而，最近 S1R 的晶体结构揭示了一个极好的机会，可以验证以前的预测，并评估新化合物的结合。有趣的是，晶体结构表明 S1R 的结合口袋高度被溶剂封闭；因此，不清楚配体如何进入该位点。在本工作中，我们应用定向分子动力学（SMD）模拟来打开 S1R 晶体结构中被封闭的配体结合口袋，并确定进入和离开结合位点的首选配体途径。β-桶配体结合区的细胞内表面被发现是容纳配体的最有利途径。该途径支持 RC-33（我们内部开发的 S1R 调节剂）和一种新的二价衍生物的结合，该衍生物构成了第一个与 S1R 相互作用的二价结构。与 S1R 相关的这些化合物的自由能计算与实验值一致，并提供了调节剂结合模式的分子见解，这些调节剂可以通过细胞质区域进入 S1R 的配体结合口袋。
