Some insights into the binding mechanism of the GABAA receptor: a combined docking and MM-GBSA study

Gamma-aminobutyric type A receptor (GABA A R) is a member of the Cys-loop family of pentameric ligand gated ion channels (pLGICs). It has been identified as a key target for many clinical drugs. In the present study, we construct the structure of human 2α 1 2β 2 γ 2 GABA A R using a homology modeling method. The structures of ten benzodiazepine type drugs and two non-benzodiazepine type drugs were then docked into the potential benzodiazepine binding site on the GABA A R. By analyzing the docking results, the critical residues His102 (α 1 ), Phe77 (γ 2 ) and Phe100 (α 1 ) were identified in the binding site. To gain insight into the binding affinity, molecular dynamics (MD) simulations were performed for all the receptor–ligand complexes. We also examined single mutant GABA A R (His102A) in complexes with the three drugs (flurazepam, eszopiclone and zolpidem) to elucidate receptor–ligand interactions. For each receptor–ligand complex (with flurazepam, eszopiclone and zolpidem), we calculated the average distance between the C α of the mutant residue His102A (α 1 ) to the center of mass of the ligands. The results reveal that the distance between the C α of the mutant residue His102A (α 1 ) to the center of flurazepam is larger than that between His102 (α 1 ) to flurazepam in the WT type complex. Molecular mechanic-generalized Born surface area (MM-GBSA)-based binding free energy calculations were performed. The binding free energy was decomposed into ligand-residue pairs to create a ligand-residue interaction spectrum. The predicted binding free energies correlated well ( R 2 = 0.87) with the experimental binding free energies. Overall, the major interaction comes from a few groups around His102 (α 1 ), Phe77 (γ 2 ) and Phe100 (α 1 ). These groups of interaction consist of at least of 12 residues in total with a binding energy of more than 1 kcal mol −1 . The simulation study disclosed herein provides a meaningful insight into GABA A R–ligand interactions and helps to arrive at a binding mode hypothesis with implications for drug design.