Molecular Docking of Phenylethylamine and CGP54626 to an Extracellular Domain of the GABA B -Receptor

Molecular docking of the extracellular domain of the GABA_B1a subunit (whose spatial structure was identified by molecular simulation of a full-size GABA_B receptor) with the GABA antagonists phenylethylamine and CGP54626 was examined. The spatial structure of the molecules of the above antagonists was obtained using the PubChem database of chemical compounds and mixtures. Detection and analysis of the interaction sites of phenylethylamine with the extracellular domain of subunit GABA_B1а of the GABA_B receptor was performed using the SwissDock web-service. Docking results were estimated using the FullFitness parameter and free energy analysis of binding of the antagonists to the receptor. The results of molecular docking of phenylethylamine and CGP54626 to the extracellular domain of subunit GABA_B1a of the GABA_B receptor, as well as a comparative analysis of these data with the results of molecular docking of baclofen to the mentioned receptor, have demonstrated that all binding sites for both antagonists and agonist, located either under or in the "claws" of the subunit molecule, are completely or partially structured by specific groups of amino acid residues. The sites differ from each other in their molecular volumes and density of filling with the above residues. According to the mentioned estimated parameters, the binding sites for baclofen, phenylethylamine, and CGP54626 located in the claws have higher motility and binding energy than similar sites positioned under the claws. In the latter case, the respective sites have higher "rigidity" and lower motility. It has been revealed that the main principle of forming the binding sites for antagonists is the formation of the main matrix elements of baclofen-binding sites located under the claws or in the latter, respectively, with subsequent creation of new groups of amino acids and/or supplying the existing ones with additional amino acid residues. As for antagonist/agonist binding sites, this process is likely to occur via the hydrogen bonds with the constituents of the former, namely amino acid residues threonine and serine, which are the most reaction-capable ones due to their hydroxylic groups. It has been assumed that one of the possible mechanisms of conformation-dependent impact of baclofen-, phenylethylamine-, and CGP54626-binding sites under the claws on the formation of sites to these compounds in the claws is based on the fact that agonist/antagonist-activated transfers of "rigidly"-packed sites, located under the claws and causing conformational transformations of polypeptide chains, are realized, in general, for greater distances. Stabilization of interaction between such sites is likely to occur via the formation of bonds between cations (positively charged radicals of polar charged amino acids in the sites under the claws) and π-electrons of aromatic rings of nonpolar and polar uncharged amino acids in the sites located in the claws.

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