痛泻要方潜在活性成分的分子靶向对接虚拟筛选研究

Study on the Molecular Targeting Docking Virtual Screening of Potential Active Components in Tong-Xie-Yao-Fang

肠易激综合征(IBS)新型药物靶标,应用分子靶向对接技术从痛泻要方化学成分中虚拟筛选具有活性潜力的天然小分子.创建了包含239种化合物的痛泻要方活性成分数据库,以色氨酸羟化酶1(TPH1),5-羟色胺跨膜转运蛋白(SERT),促肾上腺皮质激素释放因子受体1(CRFR1)和瞬时受体电位香草酸受体1(TRPV1)为对象,采用配体库构建、受体蛋白准备、对接位点研究、对接参数设定、分子对接批量打分、结合模式分析、相互作用分析、药效团分析的虚拟筛选流程.结果显示,123种天然成分显示了良好的配体-受体结合作用潜力,呈现"单靶点,多配体"的特征; Paeoniflorin、Deltoin、Naringin和β-Vatirenene等天然成分具有"单配体,多靶点"的潜力. 4-O-methyl-paeoniflorin、iso-Paeoniflorin和Gallotannin; iso-Benzoylpaeoniflorin、iso-Paeoniflorin和Benzoylpaeoniflorin; Paeoniflorin、Albiflorin R1和Albiflorin; Deltoin、Galloylpaeoniflorin、Galloylpaeoniflorine和Benzoylpaeoniflorin等13个化合物为最具潜力天然成分.药效团模型分析揭示,TPH1配体包含了2个氢键受体和3个氢键给体,SERT配体包含4个氢键受体、2个氢键给体和1个疏水中心; CRFR1配体包含1个氢键受体、2个氢键给体和1个疏水中心,TRPV1配体包含3个氢键受体和1个疏水中心.本研究为IBS治疗药物开发提供了候选化合物,并从分子水平上阐明痛泻要方作用机制提供了参考.

This study was based on a novel drug target of irritable bowel syndrome(IBS)and used molecular targeted docking technology to virtually screen promising natural small molecules from Tong-Xie-Yao-Fang.The active compound database of Tong-Xie-Yao-Fang was created,which contained a total of 239 compounds.And four proteins were selected as the targets including Tryptophan Hydroxylase 1(TPH 1),Serotonin Transporter(SERT),Corticotropin Releasing Factor Receptor 1(CRFR 1),and Transient Receptor Potential Vanilloid Receptor 1(TRPV 1).The whole process covers the ligands database construction,receptor protein preparation,docking site study,docking parameter setting,molecular docking batch scoring,binding mode analysis,interaction analysis,and pharmacophore analysis virtual screening process.The results showed that 123 of the natural compounds docked with the receptor scored the first 30%showing good ligand-receptor interaction,they present the characteristics of"single target,multiple ligands".This study also found that Paeoniflorin in the Paeoniae Radix Alba,Deltoin in the Radix Saposhnikoviae Divaricatae,Naringin in the Pericarpium Citri Reticulatae,andβ-Vatirenene in the Atractylodes Macrocephala have the most“single component,multiple targets”therapeutic potential.The results showed that 13 compounds including 4-O-methyl-paeoniflorin,iso-Paeoniflorin and Gallotannin;iso-Benzoylpaeoniflorin,iso-Paeoniflorin and Benzoylpaeoniflorin;Paeoniflorin,Albiflorin R 1and Albiflorin;Deltoin,Galloylpaeoniflorin,Galloylpaeoniflorine and Benzoylpaeoniflorin were the most promising natural compounds.The pharmacophore model analysis showed that the TPH 1 ligand contained two hydrogen bond acceptors and three hydrogen bond donors.The SERT ligand contained four hydrogen bond acceptors,two hydrogen bond donors and one hydrophobic center.CRFR 1 contained one hydrogen bond acceptor,two hydrogen bond donors and one hydrophobic center.TRPV 1 contained three hydrogen bond acceptors and one hydrophobic center.12 potential compounds were achieved through the screening process above.This study provides candidate compounds for the development of IBS therapeutic drugs and reference for exploring the molecular mechanism of Tong-Xie-Yao-Fang.