3D-QSAR Study And Molecular Dynamics Simulation Of Drug Molecules

Nowadays,the development of BigData and computer is irresistible,and the design of computer aided drug molecules is becoming more and more popular with researchers.This thesis focuses on the design of drug molecules and the theoretical simulation of biological macromolecules,which mainlyincludes:1.Combination of dopamine D3 antagonism and serotonin 5-HT1A agonism results in an effective approach to atypical antipsychotics.In this work,two predictable 3D-QSAR models were bulit for D3R antagonists and 5-HT1AR agonists,respectively.Based on the contour maps,we obtain steric and electrostatic information,and we designed four compounds with improved prediction activity.In addition,molecular docking and AD MET properties suggested that designed molecules have relatively strong interactions with receptors and low hepatotoxicity.This work sheds light on designing of novel antipsychotic drugs with increased activities of D3R and 5HT1AR simultaneously2.Dopamine D3 receptor has become an attractive target in the treatment of many diseases such as Schizophrenia,Parkinson’s and Abused drugs.3D-QSAR studies were performed on a novel series of D3 receptor antagonists,1,2,4-triazolyl 5-azaspiro[2.4]-heptanes,using CoMFA and CoMSIA.Two predictive 3D-QSAR models have been built for the modified design of D3R antagonists.Based on the contour maps,we obtain steric,electrostatic,hydrophobic and hydrogen-bond acceptor information,the key factors that affect the biological activity are studied.This work will give helpful suggestions for designing of novel D3R antagonists with increased activities.3.In recent years,transplatin damaged DNA has been a hot spot in the treatment of tumor disease.The experimental studies showed that transplatin damaged DNA could play a role in the action of PC4 protein.In this paper,molecular dynamics simulation was used to simulate the composite structure formed by the binding of transPtTz-DNA and PC4 protein.Our simulation results suggest that PC4 combined with the minor groove of DNA is more competitive than that with major groove.Residue 86 and 100 in the β sheet of PC4 form stable hydrogen bonds with DNA.Hydrogen bond between OP1@25C in DNA and HH22@86 in PC4 is the most stable one and the occupancy reaches 69.38%.