Computer Aided Drug Design(CADD) In Quantitative Structure-activity Relationship Research And The Application Of The Drug Targets To Determine

After years of development,substantial progress has been made in Computer aided drug design(CADD)field,and it has been successful in many drug research areas.With the continuous deepening of CADD application and the emergence of a variety of new methods,it has become a well developed new research field,and is more and more important in drug design areas.With its applications in Drug Design,it greatly improves the hit ratio and the speed of development of new drugs.At the same time it reduces the blindness and the chance of finding new drugs,provides a new idea and prospects of success for people to overcome some of the chronic ills.In this paper,methods of quantitative structure research activity relationship(QSAR)and molecular docking,reverse docking and other computer-aided drug design are used in anti HIV,HCV viral drug research.We establish the phenyl-aminopyridine(PAP)NNRTIs of 2D/3D-QSAR.model,forecast the panax notoginseng saponins(PNS)working on active ingredients in HCV related targets,and investigate the anti-HCV activity compounds 6-(cyclohexylmethyl)-5-ethyl-2-((2-hydroxy-2-phenylethyl)thio)pyrimidin-4-(3H)-one and binding of HCV NS5B polymerase sites.Details are as follows:1.AIDS(Acquired Immune Deficiency Syndrome)is caused by human immunodeficiency virus(HIV)epidemic diseases,it attacks the immune system helper T lymphocytes,while the body is infected with a wide variety of diseases and malignant tumors easily,in severe cases,it can cause systemic failure and death.In the face with an increasingly grim situation of AIDS prevention,it has become essential to research and develop new anti-HIV drugs with high efficiency and low toxicity.In recent years,non-nucleoside reverse transcriptase inhibitor(NNRTI)has become a rising concern due to its low toxicity and efficient,specific and structural diversity,etc.Junwon K group synthesized a series of novel Phenylaminopyridine(PAP)compounds.They can inhibit the replication of HIV at the level of micromolar,and shows good inhibitory activity for HIV reverse transcriptase.To analyze QSAR relations of these compounds,in this paper,we have choose 21 series compounds as the research object,and randomly select 16 of these compounds as a training set.we also respectively establish 2D-QSAR/3D-QSAR models and use the established models for testing the five remaining compounds activities.Accroding to the predictive values and the real values of 2D-QSAR color-coded maps and three-dimensional contour maps of 3D-QSAR analysis,We further concluded that the model established by this training set has good predictive ability and linear correlation.It provides theoretical guidance for the structural modification of these compounds.Based on the final results of the structure-activity relationship analysis,we also design a series of novel phenyl amino pyridine derivatives faction.2.Hepatitis C is a viral hepatitis caused by the hepatitis C virus(HCV)which is transmitted by blood.With increasingly close personnel exchanges,Hepatitis C is going to be a worldwide epidemic disease.So far there is still no HCV vaccine available,therefore,targets for anti-HCV virus inhibitors of small molecule drugs have emerged.Panax is a kind of traditional Chinese medicine,and Panax notoginseng saponins(PNS)is the main active ingredient,which exerts antitumor andantiviral properties.It was also found to exhibit anti-HCV replication activities with no cytotoxicity by our group.In order to find the anti HCV active components in PNS and analyze the possible mechanism of action for anti-hepatitis C,in this thesis we use panax notoginseng saponins principal component notoginseng saponin R1,ginsenoside(Rb1,Rd,Re and Rgi),and carry out molecular docking respectively with directed against HCV viral drug target NS3/4A serine protease,NS5B polymerase and protease NS5A to elucidate the possible mechanism of action.3.NS5B polymerase is an important target for anti-HCV virus,Wherein the non-nucleoside inhibitors(NNI)is attracted scientists' attention due to its high specificity.It has been found that the site of action of non-nucleoside NS5B inhibitors are mainly four,Our preliminary work has synthesized a series of 6-(cyclohexylmethyl)-5-ethy1-2-((2-hyd-roxy-2-phenylethyl)thio)pyrimidin-4-(3H)-one,they show significant inhibition of HCV replication in cells level.Since the structural similarity between these compounds and the reported NS5B inhibitor 5-cyano-6-aryl-2-thiouracil in literatures,therefore we speculate that the target of this kind of compound is also NS5B.To analyze its rationality,and provide guidance for the further optimization of the structure,in this paper the highest activity of the compounds are docked to the above four active sites respectively.The results showed that both of them present a good combination in these three active sites,which has instructional significance for the follow-up study.