Investigation of molecular interactions of prenylflavonoids at GABAA receptor subtypes
Somborac, Tamara (2019-05-23)
Investigation of molecular interactions of prenylflavonoids at GABAA receptor subtypes
(23.05.2019)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2019061220124
https://urn.fi/URN:NBN:fi-fe2019061220124
Tiivistelmä
Prenylated flavonoids derived from Hops (Humulus lupulus) activate the γ-aminobutyric acid (GABA) type A receptors through positive and negative modulation. Currently, these compounds’ binding site at the different GABAAR subtypes is still unknown.
Molecular interactions of several prenylated flavonoids were investigated at different GABAAR binding sites. The focus was on the receptor subtypes containing αβγ and αβδ subunits and the aim was to identify the most likely binding site for the prenylflavonoids by studying the relation between a ligand structure and the residues defining its putative pocket and the ligand’s calculated binding affinity.
Available GABAAR crystal structures were obtained from the Protein Data Bank, and a comparative model of the α6β3δ receptor subtype was built using the MODELLER software. The compounds were docked at the putative binding sites of the studied GABAAR subtype structures with the GLIDE tool of the Maestro molecular modeling package. An estimate of the free energy of binding was calculated with the Prime/MMGBSA tool of Maestro for all the docked receptor-ligand complexes.
The obtained results suggest that prenylflavonoids may bind to more than one pocket in the extracellular domain of the studied GABAAR subtypes. It was not possible to distinguish high affinity binding sites from low affinity binding sites as the docking results varied for each compound in the studied pockets. Discrepancy in results is likely caused by modeling binding site without knowing the correct conformations of the side chains forming the pockets. Based on the modelled α6β3δ subtype, β3δ interface may be the most likely binding site for the hops compounds. To determine the binding of the prenylated flavonoids most accurately, experimental structure determination by X-ray crystallography could be attempted.
Molecular interactions of several prenylated flavonoids were investigated at different GABAAR binding sites. The focus was on the receptor subtypes containing αβγ and αβδ subunits and the aim was to identify the most likely binding site for the prenylflavonoids by studying the relation between a ligand structure and the residues defining its putative pocket and the ligand’s calculated binding affinity.
Available GABAAR crystal structures were obtained from the Protein Data Bank, and a comparative model of the α6β3δ receptor subtype was built using the MODELLER software. The compounds were docked at the putative binding sites of the studied GABAAR subtype structures with the GLIDE tool of the Maestro molecular modeling package. An estimate of the free energy of binding was calculated with the Prime/MMGBSA tool of Maestro for all the docked receptor-ligand complexes.
The obtained results suggest that prenylflavonoids may bind to more than one pocket in the extracellular domain of the studied GABAAR subtypes. It was not possible to distinguish high affinity binding sites from low affinity binding sites as the docking results varied for each compound in the studied pockets. Discrepancy in results is likely caused by modeling binding site without knowing the correct conformations of the side chains forming the pockets. Based on the modelled α6β3δ subtype, β3δ interface may be the most likely binding site for the hops compounds. To determine the binding of the prenylated flavonoids most accurately, experimental structure determination by X-ray crystallography could be attempted.