Exploring the Binding Mechanism of GABA Receptor Agonists and Antagonists through in Silico Simulations.

GABA is a G protein-coupled receptor that functions as a constitutive heterodimer composed of the GABA and GABA subunits. It mediates slow and prolonged inhibitory neurotransmission in the nervous system, representing an attractive target for the treatment of various disorders. However, the molecular mechanism of the GABA receptor is not thoroughly understood. Therefore, a better description of the binding of existing agonists and antagonists to this receptor is crucial to improve our knowledge about G protein-coupled receptor structure as well as for helping the development of new potent and more selective therapeutic agents. In this work, we used the recent X-ray cocrystallization data of agonists (GABA and baclofen) and antagonists (2-hydroxysaclofen, SCH50911, and CGP54626) bound to the GABA orthosteric site together with quantum biochemistry and the molecular fractionation with conjugate caps (MFCC) scheme to describe the individual contribution of each amino acid residue involved in the GABA-ligand interaction, pointing out differences and similarities among the compounds. Our quantum biochemical computational results show that the total binding energy of the ligands to the GABA ligand pocket, with radius varying from 2.0 to 9.0 Å, is well-correlated with the experimental binding affinity. In addition, we found that the binding site is very similar for agonists or antagonists, showing small differences in the importance of the most significant amino acids. Finally, we predict the energetic relevance of the regions of the five ligands as well as the influence of each protein lobe on GABA-ligand binding. These results provide important new information on the binding mechanism of the GABA receptor and should facilitate the development of new chemicals targeting this receptor.