Construction Of The Effectiveness Of Anti-drug Dependence Pharmacophore Model And Virtual Screening

Drug dependence is one of the heavist social and biomedical problem in the word. Drug dependence for long time will ruin the health not only in physical but also in mental. It lead to damage personality especially, morality undone, dilinquency. The WHO declared that the number of the drug addict in the world was over284million by the end of the April,2011. Therefore, the research of drug anti-dependence is getting more and more attention, and more work focus on the searching of anti-dependence lead compounds from traditional chinese medicine （TCM）.The objective and significance of this paper:The reserve of TCM is rich.My group had ever studied on the active components of Stephania delavayi. However, the TCM used to treat drug addiction are always compound preparation, with various compounds in the medicine. Active ingredients are usually mixed with inactive ingredients, causing difficulty to quality control and limiting the use of TCM. So it is important to discover the active compounds of anti-dependence by mordern drug design methods. Using the computer-aided drug design （CADD） methods, We conducted the virtual screening of traditional chinese medicine database （TCMD） by constructing the anti-dependence pharmacophores which were based of D2and D3receptors as the structure of question in this paper. The screening results are analysed and evaluated by morecular docking and lead to the discovery of new lead compounds. The theoretical basis about the research of new anti-dependence drug will be offered fromthis paper.The main contents are as follows:1. Using HipHop method, the pharmacophore model which has anti-dependence effect was constructed by the basis of the antagonist of D2and D3receptors （D2R and D3R）. With method of receptor-ligand crystal complex model, the pharmacophore model was constructed by the basis of the D3R, which was derminded by the matching condition of training set and pharmacophore model, and examined by using training set respectively. The validity and reliability was tested and three optimal pharmacophores including D2_Ligands₀6、D3_Ligands₀3and3PBL02were confirmed.2. Using above three optimal pharmacophores to be structure of question, the virtual screening of TCMD was conducted and1181,531and1362compounds was got, respectively. The principle of Lipinski and Veber was used to eliminate the compounds which are not match to law of medicinal, and845,261and957compounds was obtained, respectively.3. Using Libdock progress, the docking of these above2063compounds and corresponding D2R and D3R was conducted. And the50compounds of best score were selected. These150compounds were subjected to more exact dock with Ligandfit docking method, and the results was evaluated by Consensus Score progress. Based on the second docking,32,16,19compounds was got respectively. 4. Based on the analysis of Consensus of these67compounds, the Flexible Docking was used to detect the mechanism of Scutellarin whose consensus score is6. Kumatakenin was selected by both D2R and D3R antagonist pharmacophores. The results presented that the combination of Scutellarin with D2R is well and stable, and the interaction energy is-60.587kJ·mol-1. Soour research showed that Scutellarin can be used as the lead compound by basis of anti-dependence antagonist of D2R theoretically Our research show that Kumatakenin combined well with D2R and D3R respectively and the interaction energy is-51.1745kJ·mol-1and-59.3854kJ·mol-1, respectively.The combination is stable. Soit can be concluded that Kumatakenin can be used as the lead compound of D2R and D3R anti-dependence theoretically.