Study On Multi-level Mechanisms Of Antidepressants And Targets

Studying the interaction mechanism between drugs and targets plays a vital role in drug development,not only improving the speed and accuracy of drug screening research,but also improving the rational design ability of new and efficient drug lead structures.In this paper,we systematically study the antidepressant mechanism of drugs and targets from different levels of multimolecules and targets to single molecules and single targets by means of systems pharmacology and molecular simulation.The main research contents and results include:（1）In order to study the mechanism of synergistic antidepressant action between drugs and targets at the multi-molecular and multi-target level,in this study,we carry out systems pharmacology study on Chaihu Shugan Powder（CSP）by applying integrated of Absorption Distribution Metabolism and Excretion（ADME）evaluation,target fishing,protein-protein interaction analysis,gene ontology enrichment analysis,establishment of a directed network and network pharmacology analysis.As a result,126 chemicals and 83 proteins are identified as active compounds and depression-related targets.In addition,CSP formula’s synergistic effects of for the treatment of depression are based on its three mechanisms,i.e.,the anti-inflammation,and the regulation of neuroendocrine system and monoamine neurotransmitter through the smooth operation of complex biological pathways,including especially PI3K-Akt,cAMP and MAPK signaling pathways.Moreover,network analysis reveals that CSP is also capable of relieving or even certainly eliminating side effects and complications of depression due to the abundant active ingredients in CSP formula.This work not only provides insights into the synergy of TCM for depression treatment,but also provides a new and effective way to develop potential antidepressants and targets.（2）In order to further study the interaction mechanism between antidepressant drugs and targets at the level of single molecules-single targets,this study takes mGluR5 negative allosteric modulators（NAMs）as an example,a set of ligand-based three-dimensional quantitative structure-activity relationship（3D-QSAR）analyses were firstly carried out applying comparative molecular field analysis（CoMFA）and comparative molecular similarity indices analysis（CoMSIA）methods.In addition,receptor-based analysis,namely molecular docking and molecular dynamics（MD）simulations,were performed to further elucidate the binding modes of mGluR5 NAMs.As a result,the optimal CoMSIA model obtained shows that cross validated correlation coefficient Q²=0.70,non-cross-validated correlation coefficient R²_ncv=0.89,predicted correlation coefficient R²_pre=0.87.Moreover,we found that aryl benzamide series molecules bind as mGluR5 NAMs at Site 1,which consists of amino acids Pro655,Tyr659,Ile625,Ile651,Ile944,Ser658,Ser654,Ser969,Ser965,Ala970,Ala973,Trp945,Phe948,Pro903,Asn907,Val966,Leu904,and Met962.This site is the same as that of other types of NAMs;mGluR5 NAMs are stabilized in the“linear”and“arc”configurations mainly through the H-bonds interactions,π–πstacking interaction with Trp945,and hydrophobic contacts.We hope that the models and information obtained will help understand the interaction mechanism of NAMs and design and optimize NAMs as new types of antidepressants.