Binding Mechanism Exploration Of Arylpiperazine Antagonists Targeting 5-HT_2A Receptor On Molecular Level

As a G-protein coupled receptor,5-hydroxytryptamine 2A(5-HT_2A)receptor is known for its critical role in the cognitive,behavioral and physiological functions,and thus is a primary molecular target to treat psychiatric diseases,including especially depression.A variety of selective serotonin reuptake inhibitors?SSRIs?have been used clinically for 5-HT_2A receptors,but their shortcomings have become increasingly apparent.Therefore,it is still necessary to explore more effective and safer drugs,and there is a lot of research work to do.With purpose to explore the structural traits affecting the inhibitory activity,currently a dataset of 109 arylpiperazine derivatives as promising 5-HT_2A receptor antagonists was built,based on which a ligand-based three-dimensional quantitative structure-activity relationship?3D-QSAR?study by using both comparative molecular field analysis?CoMFA?and comparative molecular similarity indices analysis?CoMSIA?approaches was carried out.The resultant optimal CoMSIA model displays proper reliability,good internal and external predictive abilities with cross-validated correlation coefficient Q²=0.587,non-cross-validated correlation coefficient R²_ncv=0.900 and predicted correlation coefficient for the test set of compounds R²_pre=0.897,respectively.Besides,molecular docking was also conducted to investigate the binding mode between these ligands and 5-HT_2A receptor.Meanwhile,as a docking supplementary tool to study the antagonists'conformation in the binding cavity,molecular dynamics?MD?simulation was also performed,providing further elucidation about the changes of the ligand-receptor complex in a lipid bilayer.Through a combinational use of these two methods,it is found that this scaffold of arylpiperazine derivatives exhibit an approximate"V"conformation,which fits into the conventional Site 2 of 5-HT_2A receptor by hydrogen bonds,?-?stacking and hydrophobic interactions.Lastly,some new molecules were also designed based on the above results,which may be potential arylpiperazine-based antagonists of 5-HT_2A receptor.We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antidepressant drugs as well as exploring the interaction mechanism of 5-HT_2A receptor antagonists.