合成大麻素,包括约翰·W·霍夫曼(JWH)家族的一些人,在2004年左右出现在毒品领域的“替代大麻,“尽管比大麻更有效。像Δ9-四氢大麻酚(THC),大麻中的主要精神活性成分,还发现合成大麻素与大脑中发现的大麻素受体CB1和CB2相互作用,免疫系统,和外周器官。JWH化合物和其他合成大麻素由于其滥用药物的潜力,已成为法医学界研究的重要课题,在常规药物筛选下不可检测,和不可预测的毒性。在这项研究中,活性状态CB1受体模型用于评估CB1受体与JWH合成大麻素家族配体之间的受体-配体相互作用,以及一些新设计的类似JWH的虚拟化合物,标记为MGCS化合物,使用对接,结合自由能计算(ΔG),和分子动力学模拟(MD)。计算的ΔG表明萘和吲哚之间的羰基,JWH家族的特征,N-连接的烷基链的长度是影响预测的CB1结合亲和力的两个重要结构特征,特别是增加烷基链的长度导致更好的预测结合亲和力。MD和每个残基分解结果表明,设计的具有与萘部分连接的戊基链的MGCS化合物和选择的JWH化合物与关键残基Phe170,Phe174,Phe177,Phe200,Phe268和Trp279形成了稳定且强的疏水相互作用。CB1受体。理解这些关键的相互作用可以帮助法医预测未发现的合成大麻素家族的结构。
Synthetic cannabinoids, including some from the John W. Huffman (JWH) family, emerged on the drug scene around 2004 as \"alternative marijuana,\" despite being considerably more potent than marijuana. Like Δ9-tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana, synthetic cannabinoids have also been found to interact with cannabinoid receptors CB1 and CB2, found in the brain, immune system, and peripheral organs. The JWH compounds and other synthetic cannabinoids have become important subjects of research in the forensic science community due to their drug-abuse potential, undetectability under routine drug screening, and unpredictable toxicity. In this
study, an active-state CB1 receptor model was used to assess the receptor-ligand interactions between the CB1 receptor and ligands from the JWH synthetic cannabinoid family, as well as some newly designed JWH-like virtual compounds, labeled as MGCS compounds, using docking, binding free-energy calculations (ΔG), and molecular dynamics simulations (MDs). The calculated ΔG revealed that the carbonyl group between the naphthalene and the indole, characteristic of the JWH family, and the length of the N-linked alkyl chain were two important structural characteristics that influenced the predicted CB1 binding affinity, especially as increasing the length of the alkyl chain led to better predicted binding affinity. MDs and per-residue-breakdown results showed that the designed MGCS compounds with a pentyl chain attached to the naphthalene moiety and selected JWH compounds formed stable and strong hydrophobic interactions with the key residues Phe170, Phe174, Phe177, Phe200, Phe268, and Trp279 of the CB1 receptor. Comprehension of these critical interactions can help forensic chemists predict the structure of undiscovered families of synthetic cannabinoids.