In vitro and in silico identification of the mechanism of interaction of antimalarial drug – artemisinin with human serum albumin and genomic DNA

Abstract

AbstractArtemisinins are secondary metabolites of the medicinal plant Artemisia annua, which has been traditionally used in Chinese medicine. Artemisinins have anti-inflammatory, anticarcinogenic, immunomodulatory, antimicrobial, anthelmintic, antiviral, antioxidant, and other properties. Our preliminary reverse virtual screening demonstrated that the ligand-binding domain of the human glucocorticoid receptor (LBD of hGR) is the optimal target for artemisinin. At the same time, the binding sites for artemisinin with the ligand-binding domain of the human glucocorticoid receptor coincide with those of dexamethasone. However, the pharmacokinetics, pharmacodynamics, and exact molecular targets and mechanisms of action of artemisinin are not well known. In this work, the interaction of artemisinin with human serum albumin (HSA) was studied both in vitro and in silico. The results indicate that artemisinin leads to a decrease in optical absorption and quenching of fluorescence by a static mechanism, which is similar to the effect of dexamethasone. Artemisinin interacts with Drug site I on HSA and forms a hydrogen bond with arginine 218. Retardation of the genomic DNA of sarcoma S-180 cells show that artemisinin does not interact directly with DNA. On the basis of the obtained data, we proposed a hypothetical scheme of the mechanisms of action of artemisinin.HighlightsArtemisinin quenches the fluorescence of HSA by a static mechanism.Artemisinin quenches fluorescence of tryptophan.The optimized HSA structure was obtained through molecular dynamics simulations.Artemisinin binds with HSA in Drug site I and forms a hydrogen bond with Arg218.Dexamethasone binds with HSA in Drug site I and forms hydrogen bonds with Arg218, Arg222 and Va1343.A hypothetical scheme of the mechanism of action of Artemisinin was proposed.Graphical Abstract