Investigação in silico da interação do monoterpeno 4-terpineol com o receptor GABA A.

Abstract

Considering the current gap in Epilepsy treatments, which are ineffective in 30% of cases, it is necessary to search for new compounds. The monoterpenoid terpinen-4-ol (4TRP) has demonstrated anticonvulsant activity, becoming a potencial antiepileptic drug. The emergence of new tools from Bioinformatics and Computational Biology has made it possible to evaluate in silico interactions between biomolecules, such as drug candidates and target proteins. Several anticonvulsant drugs act through γ-aminobutyric acid receptors (GABAARs), the major inhibitory neurotransmitter in nervous system. In addition, the GABAergic system is one of the main targets studied in Psychopharmacology. There is a experimental evidence of the 4TRP interaction with this pathway. This work aimed to contribute to the study of the pharmacodynamics of 4TRP through molecular docking with three-dimensional models of the GABAARs. The 4TRP enantiomers structures were obtained from ZINC database. GABAARs models obtained by comparative modeling were used in the docking simulations. Those were performed by AutoDock 4.2 configured to use the Lamarckian Genetic Algorithm with default parameters. The generated complexes were ranked in order of increasing energy, selected the top ten for each docking and analyzed in Visual Molecular Dynamics. In the docking with the GABAAR α1β2γ2 subtype, (-)4TRP showed the lowest free binding energy of -6.25 kcal/mol. Whereas (+)4TRP had the lower free binding energy of -5.89 kcal/mol. The best complex showed the interaction of 4TRP with the γ2 subunit extracellular portion. This suggests a putative binding site which is different from the benzodiazepine binding site, in accordance with existing experimental data. In the molecular docking with the δ subunit were obtained for (-) and (+) 4TRP lower free binding energies of -6.06 and -5.94 kcal/mol, respectively. The γ2 subunit is expressed in six identified GABAAR subtypes wheareas the δ subunit forms four GABAAR extrasinaptic subtypes. 4TRP is expected to interact with these subtypes. The 4TRP in silico interaction with GABAARs subtypes, as well as the experimental evidence of its relationship with the GABAergic pathway and its anticonvulsant activity indicates that a putative mechanism of action of 4TRP relates to the GABAARs γ2 and δ subunits. These results will guide future research on 4TRP pharmacodynamics and other anticonvulsants.