The Comelex Protein Structures And Interactions For Dopamine Receptors With Some Important Active Molecules

Dopamine receptors' diversity and their distribution differences in brain area lead to functional differences,so that it becomes the complex dopamine nervous system.This system plays a variety of functional roles in regulation and control of motor,emotional and cognitive activities,which are related with drug addiction,pathologies of Schizophrenia and Parkinson's disease.The different functional roles dopamine receptors exert are based on their different structures.The protein crystal structure coded with the number 3PBL is a complex protein structure of the human dopamine third receptor(D3R)and eticlopride(ETQ).D3R has a high amino acid sequence homology compared with the human dopamine first receptor(D1R),second receptor(D2R),fourth receptor(D4R),fifth receptor(D5R),and especially within the a-helices transmembrane(TM)area,it is 39.72%,82.24%,49.53%,40.65%,respectively.Therefore we use D3R as a template protein to construct other four dopamine receptor structures by homology modeling method.These five dopamine receptors are optimized by the Gromacs4.5 molecular dynamics program to obtain a number of their different conformational structures,into which the active molecules are docked to obtain a number of complex protein structures by the Dock6.0 molecular docking program.Among them,the binding energy for docking dopamine into the different conformations of five dopamine receptors is very similar with an average value of-78.2 kJ·mol-1,and for docking R-Benzedrine(R-AT)and S-Benzedrine(S-AT)the binding energies are slightly lower,with the average values of-61.10 kJ·mol-1,-60.38 kJ·mol-1,respectively;as well as for docking Ephedrine(EPH)and Pseudoephedrine(PSE),their binding energies are very close to it for docking dopamine,with the average values of-74.37 kJ·mol-1,-74.23 kJ·mol-1,respectively.But,the binding energies are different for docking other active molecules including Haloperidol(HAL),Clozapine(CLO),Risperidone(RIS),Quinpirole(QUI),Eticlopride(ETQ)into the different conformations of five dopamine receptors,which depend on the difference receptor structures to show some selective characters.The binding energies from these active molecules docked with the dopamine receptors are bigger than it for docking dopamine,which may be the intrinsic effect for them to have a regulatory fiction.The five complex protein structures of dopamine receptors with clozapine have been carried out for 10 ns by molecular dynamics simulation,after the optimization of the complex structures,every amino acid residue-clozapine complexes within a radius of 6 A around clozapine are selected and calculated with MP2/6-31G(d,p)of the G09 program.The binding energies between clozapine and D1R,or D2R,or D3R,or D4R,or D5R are-137.0,-100.0,-127.9,-136.3,-174.8 kJ-mol"1,respectively.The results showed that clozapine molecule has a strong binding energy with dopamine receptors.In this thesis,four dopamine receptors that are unknown protein structures are obtained by homologous modeling,and docked with several active molecules to obtain different docking energies to show selectivity,which is significant for providing the protein structures used to further study dopamine receptor functions.Using the Gromacs4.5 molecular dynamics program and quantum chemical method,we have studied the interactions between clozapine that is used to clinically treat schizophrenia and five dopamine receptors to demonstrate clozapine having bigger binding energies with dopamine receptors.Clozapine why to have a pharmacological effect is likely to strongly bind with the active site of dopamine receptor and to prevent excessive dopamine molecules from interacting with its receptors,because schizophrenia patients always have too dopamine molecules to exert their functions through its receptors.The results of this study can be applied to study the pathology of schizophrenia and develop related therapeutic drugs.