Study of the interaction between new triazole-derived agonists and GABAA receptors

Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain. GABA works by acting on GABA Receptors. GABAA receptors are ligand-gated ion channels that are activated by the GABA molecule and have other sites for the binding of allosteric modulators. One of the most important of these sites, is the Benzodiazepine Binding Site. Benzodiazepines act as a positive allosteric modulator of the GABAA receptor. According to role that the GABA receptor plays in the central nervous system as well as diseases related to the nervous system, the study of agonists that can play a role in modulating this receptor is very useful for pharmaceutical studies. In this study, using docking and molecular dynamic simulation method; The interaction of new triazole-based benzodiazepine agonists with GABAA receptor was investigated. To perform these steps, a PDB file with the code ۶HUP containing the human GABAA receptor structure and diazepam as the leader agonist was used. After calculating the structural parameters (such as: hydrogen bonding, gyrate radius, RMSF, RMSD) and thermodynamic parameters (such as: Gibbs free energy changes) of agonists in complex with GABAA receptor, finally agonists with desirable properties were chosen. The results of structural and thermodynamic parameters analysis were in good agreement. Selected agonists were synthesized for investigation of in vitro effects and were examined by Radio ligand receptor binding assay. In binding studies, compounds ۴c and ۵a (with Ki = ۰.۴۱nM and Ki = ۰.۴۸nM, respectively) showed the highest affinity for GABA receptor compared to Diazepam.

کلیدواژه ها:

GABA ، Allosteric modulator ، Benzodiazepine ، Docking ، Molecular Dynamic Simulation