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阿片类镇痛药作用于体内μ、δ和κ三种阿片亚型受体,是中重度疼痛的主要治疗药。目前临床上使用的阿片类镇痛药大多为μ受体激动剂,但易引起成瘾性、呼吸抑制等副作用。δ受体对μ受体介导的生理效应存在着明显的调节作用,可减少μ受体激动剂副作用的产生。因此,寻找具有μ/δ双重功效的先导化合物势必将为设计低毒副作用镇痛药物提供新的思路。借助于先进的分子模拟技术,该文首先分别构建了这两种受体激动剂的药效团模型。测试集阳性正确率(大于60%)和阴性正确率(大于90%)表明,模型具有较强的预测能力和合理性。由于从天然药物中寻找高效、低毒、无依赖性的镇痛新药已成为新的发展趋势,本课题选择在中药成分数据库中开展μ/δ阿片受体双激动剂先导化合物的虚拟筛选研究。运用空间多样性子集法,首先选取2 000个代表性中药成分作为候选分子。运用构建的2个药效团模型共同过滤,发现38个中药成分可作为潜在的μ/δ阿片受体双激动剂先导化合物。化合物与μ/δ阿片受体蛋白对接的结果显示化合物4、20、23、31、34、38与μ/δ阿片受体的结合活性较好,更有潜力作为μ/δ双重功效的阿片受体激动剂的先导化合物。其中,化合物23来源于小花木瓣树的树皮,小花木瓣树的树皮作为传统的镇痛药广泛地在非洲被使用,而化合物23有可能是其主要的镇痛成分。
Opioid analgesics act on the body of μ, δ and κ opioid receptors, is the main treatment of moderate to severe pain. At present, most of the opioid analgesics used clinically are μ-receptor agonists, but they are apt to cause side effects such as addiction and respiratory depression. δ receptor on μ receptor-mediated physiological effects there is a clear regulatory role, can reduce the μ receptor agonist side effects. Therefore, looking for lead compounds with dual functions of μ / δ will certainly provide new ideas for designing analgesics with low toxicity and side effects. With the help of advanced molecular modeling techniques, the pharmacophore model of these two receptor agonists was first constructed. The test correctness (greater than 60%) and negative accuracy (more than 90%) showed that the model has strong predictive ability and rationality. Since the search for efficient, low toxicity and non-dependence analgesic new drugs from natural medicine has become a new development trend, this subject chooses to carry out the virtual screening study of μ / δ opioid receptor dual agonist lead compounds in the database of traditional Chinese medicine components. Using the Spatial Diversity Subset Method, we first select 2 000 representative TCM components as candidate molecules. Using the constructed two pharmacophore models, we found that 38 traditional Chinese medicine components could be potential lead compounds for dual-agonist of μ / δ opioid receptor. The docking results of the compounds with μ / δ opioid receptor protein showed that compounds 4,20,23,31,34,38 had better binding activity to μ / δ opioid receptor and more potential as μ / δ double-acting opioid receptor Lead agonist compounds. Among them, compound 23 originated from the bark of the floret tree, and the bark of the fagus tree was widely used as a traditional analgesic in Africa. Compound 23 may be its main analgesic component.