Natural Coumarins And Anthraquinones From Herbs Induced The Metabolic Disorder Of Melatonin And Effective Prediction Of This Risk Using A Computational Model

Objective: Evaluate the inhibitory effects of 66 kinds of common herbs toward metabolism of melatonin,And found that Angelica dahurica and Rheum palmatum showed strong inhibition on the metabolism of melatonin.To predict the possibility of the in vivo interaction of common coumarin and anthraquinones,the kinetic inhibition type and related kinetic parameters were measured.Aim to evaluate the quantitative structure-activity relationship(QASR)between the structure of coumarin and their inhibition activity for the prediction of in vivo HDIs.To provide guidance for the rational use of melatonin in clinical.Methods:(1)In vitro experiments: Using in vitro incubation system,to evaluate the potential inhibition of different coumarin and anthraquinones toward metabolism of melatonin,and evaluate its inhibitory activity in CYP and SULT enzyme;(2)System analysis of the inhibition kinetics of metabolism of melatonin by coumarin and anthraquinones,calculating the inhibition kinetic parameters(Ki),the possible drug-drug interaction is inferred by the correlation equation;Imitating in vivo metabolic environment,to evaluate the DDI between anthraquinones and melatonin in human primary hepatocy;(3)To assay the inhibitory effect(IC50)towards coumarin,the IC50 and compound structure by comparative molecular field analysis(COMSA)and comparative molecular similarity analysis method(COMSIA)to build a model,further evaluate the quantitative structure-activity relationship(3D-QSAR)and molecular docking was used to study the binding sites of anthraquinones and CYP1A2 and SULT1A1 enzymes.Results: In the experiment,66 cmommen herbs were used to screen for the initial inhibition metabolism of melatonin,among them,Angelica dahurica and Rheum palmatum showed strong inhibition on the metabolism of melatonin.The coumarin of Angelica dahurica,including,imperatorin,isoimperatorin,phellopterin,5-Methoxypsoralen and 8-Methoxypsoralen,they exhibit a mixed inhibition toward theⅠmetabolism of melatonin with the inhibition parameters(Ki)of 14.5 n M,38.8 n M,6.34 n M,5.34 n M and 18 n M respectively.The anthraquinones of Rheum palmatum,including aloeemodin,chrysophanol,rhein,emodin and physcion,they exhibit a mixed inhibition toward theⅠmetabolism of melatonin with the inhibition parameters(Ki)of 0.16 μM,0.14 μM,0.42 μM,0.24 μM and 1.01 μM.And aloeemodin,chrysophanol and rhein exhibit a mixed inhibition toward the Ⅱ metabolism of melatonin with the inhibition parameters(Ki)of 0.20 μM,1.6 μM and 0.12 μM.The experiment which indicated a herb-drug interaction would be occurred in the co-administration of herbs or foods contains abundant coumarin or anthraquinones with melatonin.In order to further characterize the relation between the structures of coumarins and their inhibition activity toward metabolism of melatonin,a quantitative structure-activity relationship(QASR)were also performed,Co MFA model and Co MSIA model were successfully constructed for the prediction of in vivo HDIs.And molecular docking was used to study the binding sites of anthraquinones with CYP1A2 and SULT1A1 enzymes.Conclusion:1)evaluate the potential influence of common herbs on the metabolism of melatonin in vitro;2)identify the major chemical constituents(coumarins and anthraquinones)that produce marked inhibition of melatonin metabolism to further explain the underlying mechanism of the influence of coumarins and anthraquinones on melatonin and 3)characterize the quantitative structure–activity relationship(QSAR)for predicting potential risks to melatonin metabolism.Our study provides important guidance for clinical use of melatonin.