Magnoflorine alkaloid and human GABA-A receptor interaction, an in silico investigation

FANNY ALVAREZ ESCALADA; FABIANI, GISELA; LEDESMA, ANA E.

Encuentro; LI Reunion Anual de la sociedad Argentina de Biofisica; 2023

Alkaloids are organic molecules that are naturally found in plants and exhibit widebiological activity. Magnoflorine (MGF) is the most abundant aporphine alkaloid found innumerous genera of flowering plant families [1]. MGF presents two hydroxyl and twomethoxyl substituents bound to an aporphine structure with its nitrogen atom bound to asecond methyl group, which makes it a quaternary ammonium ion form with high polarityand good water solubility [2]. Biological effects of magnoflorine have been widelyreported in recent decades and some research carried out in mice suggests the possibleanxiolytic effects of magnoflorine through GABA receptor activation [3][4]. Thus, the aimsof this work is to analyze the interaction between a human GABA-A receptor andmagnoflorine alkaloid using in silico calculations.Receptor structure was obtained from the Protein Data Bank (8DD2.pdb), and dockingmolecular calculations were carried out with Autodock 4.0 program. Previously,magnoflorine structure was optimized with DFT calculations using B3LYP basis set inGaussian program package. Results obtained show that MGF interacts with GABA-Areceptor through two different binding sites, one at the extracellular interface and anothersite located in the transmembrane domain. In the extracellular region, magnoflorine islocated between the α/γ subunits, where one of the aromatic rings of the alkaloid issandwiched between two aromatic residues, α1-TYR210 and γ2-PHE77, forming π-πstacking interactions. Docking results obtained for the transmembrane domain indicatethat magnoflorine is located between helices TM2 and TM3, corresponding to the βsubunit and TM1 of the α subunit.The binding sites obtained for GABA-A receptor and magnoflorine through moleculardocking calculations agree with those previously determined for diazepam [5]. Therefore,our results would indicate that MGF could activate human GABA-A receptor, making ituseful as an anxiolytic or sedative medication.