Sweet Basil Anti-drug Dependence Of The Active Ingredient Pharmacophore Model Theory

The Chinese herbal Stephania delavayi Diels is a kind of traditional medicine, which is widely used in the south of the Yangtze River especially in south and southwest China. Its root bitter, cold, a small drug and it is effective in clearing and detoxifying, stomach pain, stasis swelling and other effects. Stephania delavayi Diels has large reserves, low prices and is rich in a large number of alkaloids, and many of them have strong biological activities such as analgesic, sedative, anti-inflammatory, some of them also have significant activity in anti-drug dependence. So it caused extensive research of scholars at home and abroad.The purpose and significance of this paper:On the basis of previous research, this paper applys the theory of quanium chemistry, molecular mechanics, molecular dynamics which is combined with computer-aided drug design(CADD) methods, in order to find the active conformations of the protoberberine-type, morphine-type and bisbenzylisoquinoline-type alkaloids in the Stephania delavayi Diels, thus determine its pharmacophore model. This paper provides theoretical basis for further study about the mechanism of anti-drug dependence, and lead compounds for anti-drug dependence development of new drugs. It will greatly accelerate the achievement of the national medicine from experience the process of transition to the theoretical science.The main contents are as follows:1. Choose human Dopamine D3receptor(DRD3)which is the most similar to Dopamine D2as a template, to build the three-dimensional structure of Dopamine D2receptor by homology modeling, MODELER program of Discovery Studio(DS)2.5software is used. After modeling, use the steepest descent method and conjugate gradient method to optimize the energy and modify the model. Then add GBIM hidden membrane and the CHARMm force field to the entire system for molecular dynamics simulations of300ps. Finally, use the Ramachandran Plot and Profile-3D program to test the quality of the model. The results show that the D2receptor structure we moded is reasonable and reliable.2. Use molecular docking simulations to study the interaction between Dopamine D2receptor and berberine-type alkaloidsits, morphine-type, and bisbenzylisoquinoline-type alkaloidsits (ligands), find the active conformations of the ligands. This artical uses Define Binding Site program of DS2.5to define the active sites of D2receptor, then uses CDOCKER program to dock ligands and receptor, greatly match their geometry and energy, in order to forecast the structures of the complexes which were made by ligands and receptor. Finally, we get the structured chart of ultimate combination. Due to the high software-evaluated scoring, we can judge that the methods we used to combine ligands and receptor are reasonable.3. Use Pharmacophore model method to determine the pharmacophore model of the Stephania delavayi Diels in the anti-drug dependence. Select six compounds which are obvious anti-drug dependence effect as training set, first use Feature Mapping program of DS2.5to find the pharmacodynamic characteristics of elements, then use Common Feature Pharmacophore Generation program to build pharmacophore model. Finally, we get the best Pharmacophore model which is based on the composite situation between the training set compounds and the pharmacophore model of key chemical characteristics. The testing set compounds verify the correctness and rationality of the model.