Methamphetamine Molecule Dopamine Receptor Protein Interaction Studies

ue to drug taking into addiction, drug molecules heavily destroy human health, resulting in many serious social problems. Why can drug molecules make various kinds of harms for human health? During which, what scientific issues should be discovered and probed?This thesis will study the interaction for methamphetatnine (ice) with dopamine3-subtype receptor (D3R) protein as an example to investigate the molecular mechanism for drug molecule to make harms for human health. The thesis is made up of three chapters.In chapter1, a brief introduction to content of drug molecules and D3R is given, in addition to an overview about the addicted mechanism by drug molecules such as opium, marijuana, methamphetamine and ecstasy (or called MDMA). D3R protein is implicated in the pathophysiology of several neurobehavieral disorders, including Parkinson's disease and other movement and hyperactivity disorders, schizophrenia, mania, depression, substance abuse, and eating disorders. D3R is a promising therapeutic target for the development of new drugs to treat them above.In chapter2, we use quantum chemistry to study the stable molecular conformations of methamphetamine, amphetamine and MDMA. There are four stable molecular conformations found for methamphetamine (ice), and through the structural alternation on the chiral carbon of ice, four pairs of (eight) stable molecular conformations are found for ice. Among them, a pair of stable ice molecular conformations, which have relative low structural energy, are used to dock into D3R protein composing four cmplex protein systems. These systems are further studied by molecular dynamics simulation and quantum chemistry to probe the interaction between ice molecule and D3R protein. Besides, four pairs of (eight) stable molecular conformations also are found for either amphetamine or MDMA respectively.In chapter3, based on the homology-modelled D3R and the crystal-built D3R as well as the stable chiral ice molecular structures, we study the interactions between methamphetamine and D3R protein. For the homology-modelled D3R, the binding energy (Eb) between R-type ice and D3R is-80.3kJ.mol-1mainly originated from the the active site residues such as Asp117, Phe203, Phe268, Phe269and Tyr191; meanwile, the value of Eb is-76.8kJ.mol-1between S-type ice and D3R, which mainly come from the active site residues such as Asp117, His272, Phe268, Phe269, Ser207, Tyrl91and Va11118. In the crystal-built D3R. the value of Eb, is-98.5kJ.mol-1between R-type ice and D3R with the active site residues such as Asp75, Cys114, Gly372, Phel97, Trp342and Tyr373:meanwile, it is-79.8kJ.mol-1between S-type ice and D3R, largely coming from the active site residues such as Asp75, Asp110, Cys114, Gly372, Phe345, Trp342and Tyr373. Most of the active site residues are the same as those for S-type ice or R-type ice structures within the two different built D3R structures. However, the strengths of interaction shown by the values of Eb for D3R interacting with R-type ice are stronger than it doing with S-type ice, although two types of ice molecues both can exist within D3R protein.Clinical resilts had demonstrated that R-type ice mainly acts as drug molecules in central nervous system, belonging to controlled drugs, and S-type ice mainly acts as drugs for curing some ills in cardiovascular system, belonging to medical drugs. Our research results indicate that the interaction is stronger for R-type ice with D3R, so that it is longer time for R-type ice to stay inside D3R as drug molecues to give the effects of poison. Contrarily, the interaction is weaker for s-type ice with D3R, so that it is easily for S-type ice to leave out of D3R, and difficult for it to act as drug molecues. These obtained results are in agreement with the clinical resilts for R-type or S-type ice. In addition, the molecular channels for different type chiral ice moving within D3R proteins need to study by using molecular dynamics simulation, and more results about the interactions between ice molecules and D3R protein will be obtained. Therefore, the mechanisms of molecular channels and molecular dynamics to be studied will further support that R-type ice belongs to controlled drugs acting in central nervous system, and S-type ice acts as medical drugs.