Avaliação in silico da interação entre o receptor GABAA e metalocompostos derivados de benzodiazepínicos

The \03B3-Aminobutyric acid type A receptor (GABAA) is the most distributed rapid-action receptor in the central nervous system (CNS). GABAA receptors are transmembrane pentameric ion channels and show high heterogeneity of their subunits. When the neurotransmitter GABA activates theses receptors, they allow the chloride ions passage into neurons, resulting in hyperpolarization of these cells, resulting in a cell hyperpolarization, making them less reactive to excitatory neurotransmitters. GABAA receptors are the target of various pharmacological groups with anaesthetic and sedative properties. The activation of these receptors can be modulated by different groups of compounds, including benzodiazepines (BZD), which have become the most widely used and prescribed pharmacological group worldwide and are prescribed for the anxiety, insomnia, muscle relaxation and epilepsy treatment. Although they are indicated for the treatment of several clinical manifestations, they may have adverse effects, such as memory impairment, discontinuation syndrome, and inefficiency in some cases of epilepsy treatment as well. In this context, it is imperative to identify and develop new compounds presenting the same classic BZD characteristics and efficiency but reducing their adverse effects. An interesting approach is the synthesis of metallocompound from the association between metallic elements and an organic compound, such as diazepam In this work, the GABAA receptor interaction between five metallocompounds derived from diazepam including palladium ion ([(DZP)PdOAcPPh3], [(DZP)PdClPPh3], [(DZP)PdClPy], ([(DZP)PdCl]2 and [(DZP)PdOAc]2) and a heteropentameric model of GABAA receptor main combination isoforms (\03B11\03B22\03B32) built using the comparative modeling technique was studied. In order to predict the ligands conformation, molecular docking simulations were performed between the diazepam-derived organometallics and the GABAA receptor model, using AutoDock software. Our results indicate that the organometallics showed lower 13 free binding energy than diazepam ligand, with emphasis on the [(DZP)PdOAc]2 compound. Four residues were identified that appear to contribute to the protein-ligand interaction: His101(\03B11), Ser204(\03B11), Tyr58(\03B32) and Phe77(\03B32).The palladium metal included in the organometallics presented a role of structural stability, providing a greater number of interactions with the GABAA receptor at the benzodiazepine site