In vitro and in silico identification of the mechanism of interaction of antimalarial drug - artemisinin with human serum albumin and genomic DNA
Artemisinins 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.\n\nHighlightsO_LIArtemisinin quenches the fluorescence of HSA by a static mechanism.\nC_LIO_LIArtemisinin quenches fluorescence of tryptophan.\nC_LIO_LIThe optimized HSA structure was obtained through molecular dynamics simulations.\nC_LIO_LIArtemisinin binds with HSA in Drug site I and forms a hydrogen bond with Arg218.\nC_LIO_LIDexamethasone binds with HSA in Drug site I and forms hydrogen bonds with Arg218, Arg222 and Va1343.\nC_LIO_LIA hypothetical scheme of the mechanism of action of Artemisinin was proposed.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC=\"FIGDIR/small/519710_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (54K):\norg.highwire.dtl.DTLVardef@cd144forg.highwire.dtl.DTLVardef@1f05519org.highwire.dtl.DTLVardef@16313aborg.highwire.dtl.DTLVardef@1a078ae_HPS_FORMAT_FIGEXP M_FIG C_FIG