Simultaneous characterization of nine isolated flavonoids in Iranian Dracocephalum species and in silico study of their inhibitory properties against MTH1 enzyme

Abstract

Dracocephalum L. is a well-known aromatic and medicinal plant genus in the Mint family. Some species of the genus such as D. kotschyi (DK) are widely used in Iranian folk medicine as tonic and carminative, as well as for relieves of headache, stomachache, and liver ailments. The present study was aimed to: isolate and determine some bioactive flavonoids from DK, evaluate their content in some Iranian Dracocephalum species, and assess their inhibitory activity and molecular dynamics against Human mutT homolog 1 (MTH1) enzyme. Aerial flowering parts of eight Iranian native Dracocephalum species were collected from different regions of Iran. The flavonoids of DK were comprehensively isolated by column chromatography, and then characterized by NMR and MS techniques. For simultaneous determination of flavonoids in methanol extract of the Dracocephalum studied species, a reversed-phase HPLC-DAD method was developed. Luteolin, apigenin, xanthomicrol, calycopterin, ermanin and three newly isolated flavonoids including circilineol, 5-demethylsinenstin, cirsimaritin and 5,7,4´-trihydroxy 3,3´-dimethoxyflavone were characterized in DK. Simultaneous determination of nine flavonoids in eight Iranian Dracocephalum species exerted the highest amount of xanthomicrol (4430±1.8 µg/g DW) and 5-demethylsinensetin (766.2±0.4 µg/g DW) in D. polychaetum and D. aucheri, respectively. Our study showed, different species with similar morphology have different flavonoid profile. To have a molecular insight into their effectiveness in cancer inhibition, Gaussian 03, GROMACS 5.2, and Pymol software were exploited to optimize, simulate, and dock them against MTH1 enzyme, respectively. Molecular docking study revealed that xanthomicrol and 5-demethylsinenstin could tightly bind to MTH1 enzyme via different hydrogen bonds in the active site of the protein. Xanthomicrol and 5-demethylsinenstin, the two flavonoids with stronger bonds with MTH1 enzyme, could be considered as reliable pharmacologically active ingredients against the cancers involving MTH1 activity.