摘要
目的基于药效团模型与正负效应双靶标分子对接策略挖掘色氨酸羟化酶1(Tryptophan hydroxylase-1,TPH1)抑制剂相关的中药活性分子。方法搭建药效团模型、类药性筛选、药代动力学预测、双靶标分子对接、分子动力学模拟于一体的药物筛选平台,从TCM@TAIWAN数据库中发现新型TPH1候选抑制剂。结果命中分子ZINC85626251、ZINC85626260实验数据均表现出良好的抑制活性及类药性,预测命中分子可有效抑制胃肠道相关的TPH1活性,但对中枢神经系统相关TPH2活性抑制作用较小,并精准预测靶标与命中分子的结合自由能及相互作用方式。结论整合多种计算机虚拟筛选技术挖掘TPH抑制剂,从天然产物中挖掘到2个缓解肠易激综合征相关痛症的潜在的活性分子ZINC85626251、ZINC85626260。
Objective Mining Tryptophan hydroxylase-1(TPH)inhibitors from traditional Chinese medicine using pharmacophore model and the dual-target molecular docking with positive and negative effects.Methods A computer virtual drug screening platform integrating pharmacophore model,drug-like screening,ADME prediction,dual-target molecular docking,and molecular dynamics simulation was built to discover potential TPH1 inhibitors from TCM@TAIWAN database.Results Two candidate molecules ZINC85626251,ZINC85626260 were screened from the database TCM@TAIWAN,both of them were predicted with good inhibitory activity and drug-like properties.Results of the docking scoring showed that,each candidate molecule has strong inhibitory effect on the gastrointestinal related target TPH1;but the inhibitory effect on the target TPH2 is weak,which effectively avoids the negative effect of central nervous system-related TPH2 enzyme activity inhibition.Finally,highly precise binding free energy between THP1 target and candidate chemical compound and various energy contributions were determined by molecular dynamics simulation and MM/PBSA algorithm.Conclusion A variety of computer virtual screening technologies were comprehensively integrated to discover novel TPH inhibitors,and two potential active molecules that can relieve pain associated with irritable bowel syndrome were discovered from natural products.
作者
史海龙
史永恒
王川
程怡
黄月
刘继平
王斌
SHI Hailong;SHI Yongheng;WANG Chuan;CHENG Yi;HUANG Yue;LIU Jiping;WANG Bin(Shaanxi University of Chinese Medicine,Xixian New Area 712046 Shaanxi,China)
出处
《中药新药与临床药理》
CAS
CSCD
北大核心
2021年第7期959-968,共10页
Traditional Chinese Drug Research and Clinical Pharmacology
基金
陕西省中医管理局中医药科研课题(JCMS003)
陕西省自然科学基础研究计划项目(2019JQ-401)
陕西中医药大学创新团队项目(2019-YL13)。
关键词
药效团模型
分子对接
分子动力学模拟
色氨酸羟化酶
抑制剂
肠易激综合征
痛症
潜在活性分子
Pharmacophore model
molecular docking
molecular dynamics simulation
tryptophan hydroxylase
inhibitor
irritable bowel syndrome
pain
potential active molecule
