Modeling of peroxide activation in artemisinin derivatives by serial docking.

Serial docking of artemisinin derivatives. A serial docking study was undertaken with the purpose to improve the understanding of the mechanism of production of biological activity in Artemisinin derivatives. The Heme molecule receptors were primarily chosen to represent the changing binding and oxidation states of this molecule, which are postulated to occur during the activation of the drug, in order to relate these results to the observed biological activity. The results of the docking runs were classified according to similarity to a standard orientation by a combination of automated and "by hand" procedures. One- and two-dimensional QSAR equations were used in an exploratory sense in order to study the influence of the type of receptor. Principal component and partial least squares regression techniques were used in the case of the multivariate (3D-QSAR) descriptors. The results obtained corroborate the postulated mechanism of production of biological activity as well as providing evidence that, at the moment of activation, the electronic structure of the Heme molecule approximates that of the oxygenated Heme, the drug molecule adopts a preferred orientation, and that, in addition to the important positive contribution of the O(1) - Fe interaction, there is as well a significant negative effect on the biological activity by carbons 4 - 6 of the artemisinin ring system.