Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
NIH National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Acta Pharmacol Sin. 2019 Mar;40(3):374-386. doi: 10.1038/s41401-018-0071-1. Epub 2018 Sep 10.
With treatment benefits in both the central nervous system and the peripheral system, the medical use of cannabidiol (CBD) has gained increasing popularity. Given that the therapeutic mechanisms of CBD are still vague, the systematic identification of its potential targets, signaling pathways, and their associations with corresponding diseases is of great interest for researchers. In the present work, chemogenomics-knowledgebase systems pharmacology analysis was applied for systematic network studies to generate CBD-target, target-pathway, and target-disease networks by combining both the results from the in silico analysis and the reported experimental validations. Based on the network analysis, three human neuro-related rhodopsin-like GPCRs, i.e., 5-hydroxytryptamine receptor 1 A (5HT), delta-type opioid receptor (OPRD) and G protein-coupled receptor 55 (GPR55), were selected for close evaluation. Integrated computational methodologies, including homology modeling, molecular docking, and molecular dynamics simulation, were used to evaluate the protein-CBD binding modes. A CBD-preferred pocket consisting of a hydrophobic cavity and backbone hinges was proposed and tested for CBD-class A GPCR binding. Finally, the neurophysiological effects of CBD were illustrated at the molecular level, and dopamine receptor 3 (DRD3) was further predicted to be an active target for CBD.
鉴于 CBD 的治疗机制仍不清楚，因此系统地鉴定其潜在靶点、信号通路及其与相应疾病的关联，对研究人员来说非常有意义。在本工作中，我们应用基于化学基因组知识库的系统药理学分析，通过将计算机分析结果和已报道的实验验证结果相结合，进行系统的网络研究，生成 CBD 靶标、靶标通路和靶标疾病网络。基于网络分析，选择了三种人类神经相关的视紫红质样 G 蛋白偶联受体，即 5-羟色胺受体 1A（5HT）、delta 型阿片受体（OPRD）和 G 蛋白偶联受体 55（GPR55），进行了深入评估。我们采用了包括同源建模、分子对接和分子动力学模拟在内的综合计算方法，来评估蛋白-CBD 结合模式。提出了一个由疏水腔和骨架铰链组成的 CBD 优先结合口袋，并对其进行了 CBD 类 A GPCR 结合的测试。最后，从分子水平说明了 CBD 的神经生理效应，并进一步预测多巴胺受体 3（DRD3）是 CBD 的一个活性靶标。
