具有μ/δ双重功效的阿片受体激动剂中药成分筛选研究

Virtual Screening of Chinese Medicine in μ/δ Dual Action Opioid Receptor Agonist

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 as a kind of potent pain-killer mainly affect μ, δ and κ three opioid receptor subtypes. At present, μ opioid receptor agonists were widely used in clinical treatment, but undesired side effects such as physical dependence, respiratory depression limit the use. δ receptors can modulate the physiological effects of μ receptor and reduce the side effects of μ receptor agonist. Therefore, seeking a new μ/δ dual action opioid receptor agonist lead compound will provide a new way for finding analgesics with low toxicity and fewer side effects. With advanced molecular simulation technique, pharmacophore models of both μ/δ receptor agonists were built in our study. Positive accuracy （over 60%） and negative accuracy （over 90%） indicated that models showed preferable prediction ability. Finding high efficiency and low toxicity analgesic from nature product has become a new trend. We performed virtual screening of μ/δ dual action opioid receptor agonist through traditional Chinese medicine database. Diverse subset was utilized to select 2000 compounds as candidates. Pharmacophore models were further employed to obtain 38 compounds which were taken as potential μ/δ dual action opioid receptor agonists. The result of molecular docking indicates that compounds 4, 20, 23, 31, 34, 38 are more like to be μ/δ dual action opioid receptor agonist. Among them, compound 23 derived from the bark of Xylopia parviflora is used as traditional medicine for analgesia in Africa. This study suggests that compound 23 might be the main active ingredient for analgesia.