Pharmacology and Therapeutic Group, Faculty of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia.
Pharmacology and Therapeutic Group, Faculty of Pharmaceutical Sciences, University of Cartagena, Cartagena, Colombia; GINUMED, Faculty of Medicine, Rafael Nuñez University Corporation, Cartagena, Colombia.
Comput Biol Chem. 2021 Dec;95:107590. doi: 10.1016/j.compbiolchem.2021.107590. Epub 2021 Oct 12.
Cannabis sativa has been attributed to different pharmacological properties. A number of secondary metabolites such as tetrahydrocannabinol (THC), cannabinol (CBD), and different analogs, with highly promising biological activity on CB and CB receptors, have been identified.
Thus, this study aimed was to evaluate the activity of THC, CBD, and their analogs using molecular docking and molecular dynamics simulations (MD) methods. Initially, the molecules (ligands) were selected by bioinformatics searches in databases. Subsequently, CB and CB receptors were retrieved from the protein data bank database. Afterward, each receptor and its ligands were optimized to perform molecular docking. Then, MD Simulation was performed with the most stable ligand-receptor complexes. Finally, the Molecular Mechanics-Generalized Born Surface Area (MM-PBSA) method was applied to analyze the binding free energy between ligands and cannabinoid receptors.
The results obtained showed that ligand LS-61176 presented the best affinity in the molecular docking analysis. Also, this analog could be a CB negative allosteric modulator like CBD and probably an agonist in CB like THC and CBD according to their dynamic behavior in silico. The possibility of having a THC and a CBD analog (LS-61176) as a promising molecule for experimental evaluation since it could have no central side-effects on CB and have effects of CB useful in pain, inflammation, and some immunological disorders. Docking results were validate using ROC curve for both cannabinoids receptor where AUC for CB1 receptor was 0.894±0.024, and for CB2 receptor AUC was 0.832±0032, indicating good affinity prediction.
大麻已被归因于不同的药理特性。已经鉴定出许多次级代谢物，如四氢大麻酚（THC）、大麻酚（CBD）和不同的类似物，它们对 CB 和 CB 受体具有高度有前途的生物活性。
因此，本研究旨在使用分子对接和分子动力学模拟（MD）方法评估 THC、CBD 和它们的类似物的活性。最初，通过数据库中的生物信息学搜索选择分子（配体）。随后，从蛋白质数据库数据库中检索 CB 和 CB 受体。然后，优化每个受体及其配体以进行分子对接。然后，对最稳定的配体-受体复合物进行 MD 模拟。最后，应用分子力学-广义 Born 表面积（MM-PBSA）方法分析配体与大麻素受体之间的结合自由能。
所得结果表明，配体 LS-61176 在分子对接分析中表现出最佳亲和力。此外，根据其在计算机中的动态行为，该类似物可能像 CBD 一样是 CB 的负变构调节剂，并且可能像 THC 和 CBD 一样是 CB 的激动剂。由于它可能对 CB 没有中枢副作用并且对疼痛、炎症和一些免疫性疾病具有 CB 的有用作用，因此 LS-61176 作为有前途的实验评估分子是有可能的。 THC 和 CBD 类似物（LS-61176）的对接结果使用两种大麻素受体的 ROC 曲线进行验证，其中 CB1 受体的 AUC 为 0.894±0.024，CB2 受体的 AUC 为 0.832±0032，表明良好的亲和力预测。
