flavin-adenine-dinucleotide and artemisinin

It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health.

Topics: Amino Acid Sequence; Antimalarials; Artemether; Artemisinins; Artesunate; Drug Design; Flavin-Adenine Dinucleotide; Global Health; Humans; Molecular Docking Simulation; Molecular Sequence Data; NADH Dehydrogenase; Plasmodium falciparum; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Protozoan Proteins; Sequence Homology, Amino Acid; Static Electricity; Thermodynamics; Tumor Protein, Translationally-Controlled 1