title: Structural insights into the theoretical model of Plasmodium falciparum NADH dehydrogenase and its interaction with artemisinin and derivatives: towards global health therapeutics.
abstract: 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.
authors: Department of Bioinformatics, Applied Botany Centre, University School of Sciences, Gujarat University, Ahmedabad, India.
authors: Sivakumar Prasanth
authors: SP
authors: Kumar
authors: Yogesh T
authors: YT
authors: Jasrai
authors: Himanshu A
authors: HA
authors: Pandya
authors: Linz-Buoy
authors: LB
authors: George
authors: Saumya K
authors: SK
authors: Patel
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry*; D000077549:Artemether; D037621:Artemisinins / Q000737:chemistry*; D000077332:Artesunate; D015195:Drug Design; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry; D014943:Global Health; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013816:Thermodynamics; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; D005182:Flavin-Adenine Dinucleotide; D000077332:Artesunate; C031327:artemisinin; D000077549:Artemether; D009245:NADH Dehydrogenase