Discovery of potentially biased agonists of mu-opioid receptor (MOR) through molecular docking, pharmacophore modeling, and MD simulation
Discovery of potentially biased agonists of mu-opioid receptor (MOR) through molecular docking, pharmacophore modeling, and MD simulation
复制标题
通过分子对接、药效团建模和 MD 模拟发现潜在偏向的 mu-阿片受体 (MOR) 激动剂
DOI：
10.1016/j.compbiolchem.2020.107405
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发表时间：
2021-02-02
影响因子：
3.1
通讯作者：
Wang, Liang-Liang
中科院分区：
文献类型：
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作者：
Jiang, Xuan;Li, Shuxiang;Wang, Liang-Liang
众所周知，阿片类药物具有强效镇痛功效和严重副作用。研究表明，镇痛作用由μ阿片受体（莫尔）下游的G蛋白依赖性通路介导，另一条β-arrestin依赖性通路介导呼吸抑制、便秘和耐受等副作用。TRV 130是G蛋白依赖性通路的偏性配体，镇痛作用强，且副作用比吗啡少。在这项研究中，使用Oliceridine（TRV 130）和PZM 21作为模板，在IBSSC数据库中进行结构相似性检索。建立了基于三维结构的药效团模型，并采用组合式分子对接预测模式筛选小分子，最后根据亲和力预测得到4个候选分子。分子动力学模拟探索了动力学条件下蛋白质与小分子相互作用的详细机制。这些结果表明，这些候选分子是潜在的莫尔激动剂。
Opioids are well known for their potent analgesic efficacy and severe side effects. Studies have shown that analgesic effects are mediated by the downstream G-protein-dependent pathway of the mu-opioid receptor (MOR), and another beta-arrestin-dependent pathway mediates side effects such as respiratory depression, constipation and tolerance etc. TRV130 is a biased ligand for G-protein-dependent pathway, which has high analgesia and has fewer side effects than morphine. In this study, the structure similarity search was performed on the IBSSC database using Oliceridine (TRV130) and PZM21 as templates. The 3D structure-based pharmacophore model was built and combined molecular docking prediction mode was selected to filter out small molecules, Finally, based on affinity prediction, four candidate molecules were obtained. Molecular dynamics simulations explored the detailed interaction mechanism of proteins with small molecules under dynamics. These results suggest that these candidate molecules are potential MOR agonists.