Study On The Quantitative Structure-Activity Relationship Of Artemisinin Analogs

Based on the novel antimalarial receptor PfATP6, the three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) of 40 artemisinin relatives and 43 1,2,4-trioxolanes were studied. The following works were done in this thesis.The QSAR studies of 40 artemisinin relatives were conducted by Flexible Docking Technology (program FlexX 1.13.2) and Comparative Molecular Field Analysis (CoMFA). Two kinds of CoMFA model including the docking CoMFA model and the database align CoMFA model were built. From the Partial Least Square (PLS) analysis, we found that the docking CoMFA was much better in analyzing QSAR and predicting the activities of artemisinin relatives. At last,the docking CoMFA model was investigated. The steric & electrostatic contour maps indicated that steric bulk surrounding C-13 would increase the activity while steric occupancy with bulk groups around C-14 would decrease the activity. On the other hand, high electron density around O-15 had a favorable effect on the activity of an analog while negative charge surrounding C-14 was disfavorable to the activity.We chose the active conformations by FlexX, and from the docking study we also concluded that the hydrophobic interaction of artemisinin relatives with PfATP6 would increase the combination of the analog-PfATP6 complex. The hydrogen bonding formed by the oxygen in peroxide and the hydrogen in amino acid residue Ile1041 stabilized the complex.The CoMFA model of the 1,2,4-trioxolanes was formed by simulated annealing and docking alignment. Because of the diversity in molecule structure and the scarcity of the kind of analogs, no useful CoMFA model was established. To improve it,we need to add more molecules in our system and classify them.