Computational Modeling of Artemisinin and its structural derivatives Interaction Activity and Mechanism

Abstract

Artemisinins are the most potent antimalarials available, rapidly killing all asexual stages of P. falciparum. They are sesquiterpene lactones, widely used to treat multidrug-resistant malaria. Thus it was the objective of numerous studies to prepare better and safer anti-malarial drugs. However, the mode of action of this antimalarial is not fully understood. Artemisinins act via mechanisms that are distinct from other antimalarial classes, including those that inhibit well defined targets such as enzymes of folate biosynthesis, the DOXP reductase pathway or the cytochrome electron transport system. The peroxide within the 1,2,4-trioxane system of artemisinins is essential for antimalarial activity. Therefore, the peroxide structure becomes a focus for considerable chemical analysis aimed at trying to understand how artemisinins work. There were two mode of action of artemisinin proposed. One of the activated artemisinins form adducts with heme and leads to inhibition of heme polymerization. Secondly as shown recently, artemisinins, but not quinine or chloroquine, inhibit the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) orthologue (PfATP6) of P. falciparum. PfATP6 is essential for P. falciparum calcium homeostasis. However the mechanism of interaction as well as the binding affinity of artemisinin with heme and PfATP6 has not yet known. In this regard the molecular modeling study could be very helpful to explore the mode of interaction. Docking, binding free energy and quantitative structure activity relationship (QSAR) are computational ways to explore the binding structure, binding affinity, interaction of ligand/receptor and development of activity model. In this work, several computational approaches were used to explore the binding of artemisinin and its structural derivatives in heme and PfATP6. newline