Gaba Receptors And The Study Of Interaction Between Ligands

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitterin the mammalian central nervous system (CNS). GABA receptor is thetarget of a variety of pesticides such as fipronil, avermectin, and it alsoassociated with a variety of human mental diseases. The interactionbetween GABA receptor and small molecules is very important.However, because of the membrane proteins purification technologylimits, the crystal structure of GABA receptor has not been reported.Here, we here built the models of GABA a type receptor (GABAaR) andits mutants, to study the machenism when docking with ligands bycomputer aided simulation.Firstly, we built rat GABAaR model basing on the crystal structure ofacetylcholine binding protein (AChBP) by homology modeling. Theinfluence of important amino acid mutations on ligand-receptorbinding was studied by docking. It was found that amino acidmutations may affect the cation-π interactions between the receptorsand ligand, such as mutation of β97Tyr, binding capacity betweenreceptors and ligand will increase with the increment of the fluorineatoms; and it also affected the hydrogen bonding interactionsbetween the ligands and receptors, such as mutation of β157Tyr andβ205Tyr, mutant receptors were no longer suitable for hydrogen bondacceptor, the combination between receptor and ligand washampered.Secondly, we used the nicotinic acetylcholine receptor (nAChR) asa template to build the human β3homologous pentamer model byhomology modeling. After docking this model with a series of fipronilderivatives, three small ligands were selected basing on lower dockingenergy, which match with the bioassay result.The novelties of this paper were using computer simulation to build the mutations of GABA receptors, first time introducing fluorine atomsinto amino acids, which were not exist in nature, explaining the impactof mutations of amino acids on the biological activity of small moleculeligands in the perspective of the cation-π bridge, further explaining thechange of biological activity while the change of amino acid in themolecular level.