The Molecular Modelling Study On Interaction Between Novel Antidepressants And Their Targets

Depression has become the fourth disease in the world mainly characterized by low moods and spirits with autonomic nerve or somatic symptoms,which are harmful to human physical and psychological health.Recently,the common used antidepressants like TCAs,SSRIs and SNRIs are ineffective to 30%-40%of patients,and there exsit the delayed actions,significant toxic side effects and poor tolerability.Therefore,seeking safety and effectiveness and solving the delayed action problem are the orientation of antidepressants research.Herein,we have made a detailed research on the mechanism of novel antidepressants NRIs with their target hNET,explained the molecular selectivity of ligands for hSERT versus hNET,and investigated the mechanism of acion of vilazodone with 5-HT_1A receptor agonism and hSERT inhibition at atomic level,thus aiming at laying a theoretical basis for novel antidepressants design.1.The study on the mechanism of NRIs action on hNET.4 NRIs atomoxetine,maprotiline,reboxetine,and viloxazine were selected as representatives and molecular docking and MD simulation followed by binding free energy analysis have been adopted.The stability and accuracy of the model have been verified from the aspects:mutagenesis and crystal structure comparative analysis.The results indicated that our simulations were reliable and accurate,and 11 residues（F72,D75,A145,V148,G149,Y152,F317,F323,S419,S420,and G423）in hNET have been identified to play a vital role in NRIs binding to hNET.2.The study on the molecular selectivity of hSERT versus hNET.The escitalopram（SSRI）,talopram（NRI）and its analog（SNRI）with structurally similar skeleton have been chosen as probes.The molecular selectivity of 3 ligands for hSERT versus hNET has been elucidated via MD simulation,followed by binding free energy calculation,energy-structure relationship analysis and protein-ligand interaction fingerprints analysis.It showed that the molecular selectivity of ligand was mainly originated from warm spots rather than hot spots.The warm spots were located on TM3,TM8 and TM10regions of hSERT or hNET.For hNET,7 residues（A73,A145,Y151,S420,M424,A477 and I481）on hNET had a great effect on molecular selectivity.Enhancing the interaction of ligands with residues（A73,Y151,A477 and I481）or the weakened interaction of ligands with residues（S420 and M424）might improve the ligands selectivity for hNET.For hSERT,9 residues（A96,A169,A173,Y175,F335,T439,L443,T497 and V501）had a great impact on molecular selectivity.The enhanced interaction of ligands with residues（A96,A173,T439 and L443）or the weakened interaction of ligands with residues（Y175,T497 and V501）may strengthen the ligands selectivity for hSERT.3.The study on the mechanism of vilazodone action on 5-HT_1A receptor and hSERT.Vilazodone not only can inhibit the activity of hSERT,but also can agonize 5-HT_1A receptor.It works via dual mechanism targeting transporter and receptor.With respect to mechanism of vilazodone action on 5-HT_1A receptor,vilazodone and its 50analogs were selected as representatives,and Prime/MM-GBSA method was adopted to choose the initial poses.The chosen 6 complexes（14,29,36,39,48 and 51）had been subject to MD simulation and then the analysis including binding free energy calculation,energy decomposition,and alanine scanning mutagenesis were utilized to investigate the mechanism of vilazodone action on 5-HT_1A receptor.As a consequence,22 residues(M92^2.60,A93^2.61,Y96^2.64,W102^ECL1,C109^3.25,F112^3.28,I113^3.29,D116^3.32,V117^3.33,S119^3.35,C120^3.36,T121^3.37,T188^ECL2,I189^ECL2,T196^5.39,T200^5.43,A303^5.46,W358^6.48,F361^6.51,F362^6.52,N386^7.39 and Y390^7.43)in 5-HT_1A receptor have been discovered to be crucial for vilazodone binding to receptor.In terms of vilazodone binding to hSERT,vilazodone and its 5 derivatives（15,20,22,39 and 47）were chosen and the crystal structure of hSERT（PDB ID:5I73）was selected as a start.MD simulation has been carried out on 6 complexes and then protein-ligand interaction fingerprints analysis has been applied to explore the mechanism of vilazodone action on hSERT.It suggested that 11 residues（Y95,D98,R104,I172,Y175,Y176,F335,F341,S438,T439 and E493）on hSERT have been found to be important for vilazodone binding to hSERT.Besides,vilazodone occupied the S1 and S2 binding site within hSERT at the same time,and the ionic switch（R104/E493）between S1 and S2 binding pocket was in open state when binding to hSERT.In this study,the mechanism of novel antidepressants action on their targets could provide a theoretical guidance for designing antidepressants with novel scaffolds,quick therapeutic effects,and fewer side effects,and also offer an innovative perspective and strategy for designing antidepressants with a new mechanism.