Manandhar Anjela, Haron Mona H, Klein Michael L, Elokely Khaled
Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.
National Center for Natural Products Research, University of Mississippi, Oxford, MS 38677, USA.
Life (Basel). 2022 Dec 18;12(12):2137. doi: 10.3390/life12122137.
The cannabinoid receptors CBR and CBR are members of the G protein-coupled receptor (GPCR) family. These receptors have recently come to light as possible therapeutic targets for conditions affecting the central nervous system. However, because CBR is known to have psychoactive side effects, its potential as a drug target is constrained. Therefore, targeting CBR has become the primary focus of recent research. Using various molecular modeling studies, we analyzed the active, inactive, and intermediate states of both CBRs in this study. We conducted in-depth research on the binding properties of various groups of cannabinoid modulators, including agonists, antagonists, and inverse agonists, with all of the different conformational states of the CBRs. The binding effects of these modulators were studied on various CB structural features, including the movement of the transmembrane helices, the volume of the binding cavity, the internal fluids, and the important GPCR properties. Then, using in vitro experiments and computational modeling, we investigated how vitamin E functions as a lipid modulator to influence THC binding. This comparative examination of modulator binding to CBRs provides significant insight into the mechanisms of structural alterations and ligand affinity, which can directly help in the rational design of selective modulators that target either CBR or CBR.
大麻素受体CBR和CBR是G蛋白偶联受体（GPCR）家族的成员。这些受体最近作为影响中枢神经系统疾病的潜在治疗靶点而受到关注。然而，由于已知CBR具有精神活性副作用，其作为药物靶点的潜力受到限制。因此，靶向CBR已成为近期研究的主要焦点。在本研究中，我们使用各种分子建模研究分析了两种CBR的活性、非活性和中间状态。我们对包括激动剂、拮抗剂和反向激动剂在内的各类大麻素调节剂与CBR所有不同构象状态的结合特性进行了深入研究。研究了这些调节剂对各种CB结构特征的结合作用，包括跨膜螺旋的移动、结合腔的体积、内部流体以及重要的GPCR特性。然后，通过体外实验和计算建模，我们研究了维生素E作为脂质调节剂如何影响THC结合。这种对调节剂与CBR结合的比较研究为结构改变和配体亲和力机制提供了重要见解，这可以直接有助于合理设计靶向CBR或CBR的选择性调节剂。
