Studies Of The Interaction Between Artemisinins And P-gp And The Anti-malarial QSAR Of Artemisinin

Artemisinin is an excellent anti-malarial drug discovered by Prof.Youyou Tu from China,which has high efficiency and low toxicity.The discovery of artemisinin has made a great contributions to the control and treatment against malaria around the whole world.Continued research on artemisinins revealed that artemisinins exert not only antimalarial activity,but also has other pharmacological activities such as antitumor,anti-inflammatory,regulating body immunity,and antiarrhythmia.P-glycoprotein（P-gp）is an active drug efflux pump,which exists widely in various MDR tumor cells,conferring drug resistance to tumor cells during chemotherapy.The 23 10-phenyl ether artemisinin compounds are novel anti-tumor compounds.The aim of this study was to evaluate the transport activity of P-gp towards the 10-O-phenyl DHA ethers and the transport inhibition activities of the compounds to P-gp,which could provide crucial information for the further development on the compounds.The results indicated that 10-O-phenyl DHA ethers showed different types of interaction with P-gp,either as inhibitors or substrates of P-gp or exerting poor interaction with P-gp.Computer simulation results indicated that the10-O-phenyl DHA ethers share the same binding pocket mainly composed of Arg262,Ser429,Arg527,Tyr1044 and His1232.Furthermore,the minimum binding energy of the DHA derivatives with P-gp exhibited significant correlations with the inhibitory activity to P-gp mediated doxorubicin efflux,which imply that the binding sites of 10-O-phenyl DHA ethers on P-gp should interact with those responsible for doxorubicin transport directly.the10-O-phenyl DHA ethers interacting with P-gp at the tail group but exhibiting no interaction at the head group exhibited a significant potential to overcome P-gp mediated MDR.the10-O-phenyl DHA ethers had the potential to overcome or even reverse multidrug resistance in tumors.The research had important research significance on the mechanism of artemisinin antitumor and the design of new drugs.At the same time,the research in this thiesis could provide important theoretical support for the design of artemisinins based combinational therapy protocol against tumor in clinical practice.Artemisinin has high antimalarial activity withpoor water solubility.Therefore,it is necessary to improve the pharmacokinetic properties for better clinical efficacy.The research on the modification of artemisinin pharmacokinetics mainly focuses on C-10 and O-11.An accurate and reliable 3D QSAR model for antimalarial activity of C-10 and O-11 artemisinin derivatives could provide effective information for the the modification on artemisinin for better pharmacokinetic properties.The 3D QSAR studies on 50 C-10 and O-11 artemisinin derivatives were performed using 3D-QSAR module in Discovery Studio.The resulting QSAR model exhibited a high cross-validation coefficient（q²）of 0.532,a non-cross-validation coefficient（r²）of 0.997 and a predictive correlation coefficient(r²_pred)of 0.777.The results indicated that the introduction of longer side chains with fewer branches on the 10-C of artemisinin,or the change of 11-O to nitrogen heterocycle,and the modification of the electronegativity on the nitrogen with small steric hindrance may increase its antimalarial activity.This model is accurate and reliable,which could provide valid theoretical basis for the studies on the improvement of pharmacokinetics properties of artemisinins.