目的 基于计算机模拟技术从中药天然产物库中挖掘色氨酸羟化酶1(tryptophan hydroxylase-1,TPH1)抑制剂。方法 搭建分子对接、类药性筛选、药动学预测、分子动力学模拟于一体的药物筛选平台,从中药系统药理学数据库与分析平台(traditional chinese medicine systems pharmacology database and analysis platform,TCMSP)数据库中挖掘TPH1抑制剂。结果 川贝酮碱(TCMSP_ID:MOL009572)实验数据均表现出良好的TPH1抑制活性及类药性,预测命中分子可有效抑制胃肠道相关TPH1活性,但对中枢神经系统相关TPH2活性抑制作用较小;通过酶活抑制实验验证抑制效应,并借助分子动力学模拟动态解析结合能变化及各项能量分布。结论 整合多种虚拟筛选技术挖掘到缓解肠易激综合征相关痛症的TPH1抑制剂-川贝酮碱MOL009572。

Objective To discover the active molecules with inhibitory activity to tryptophan hydroxylase-1 (TPH1) from traditional Chinese medicine natural product database based on computer simulation technology. Methods A drug screening platform, that integrates molecular docking, drug-like screening, pharmacokinetic prediction, and molecular dynamics simulation, was built to discovery TPH1 inhibitors from the TCMSP database. Results Chuanbeinone (TCMSP_ID:MOL009572) showed good inhibitory activity to TPH1 and drug-likeness, which can effectively inhibit gastrointestinal related TPH1 enzymes, but had weak inhibitory effect on central nervous system-related TPH2 enzyme activity.Through preliminary verification of enzyme activity inhibition, molecular dynamics simulation is used to accurately predict the free binding energy of THP1 and MOL009572 and various energy contributions. Conclusion Chuanbeidone, MOL009572, an active molecule of traditional Chinese medicine that relieves irritable bowel syndrome-related pain, has been screened out through integrated multiple virtual screening technologies.

R284.1

陕西省中医管理局中医药科研课题（JCMS003）；陕西中医药大学创新团队项目（2019-Y505）