Some insights into the binding mechanism of the GABA(A) 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 2 alpha(1)2 beta(2)gamma(2) GABAAR 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 GABAAR. By analyzing the docking results, the critical residues His102 (alpha(1)), Phe77 (gamma(2)) and Phe100 (a1) 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 GABAAR (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 Ca of the mutant residue His102A (a1) to the center of mass of the ligands. The results reveal that the distance between the Ca of the mutant residue His102A (a1) to the center of flurazepam is larger than that between His102 (a1) 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 (a1), Phe77 (gamma(2)) and Phe100 (a1). These groups of interaction consist of at least of 12 residues in total with a binding energy of more than 1 kcalmol-1. The simulation study disclosed herein provides a meaningful insight into GABAAR-ligand interactions and helps to arrive at a binding mode hypothesis with implications for drug design.
homology modeling molecular mechanic-generalized born surface area gamma-aminobutyric acid type a receptors molecular dynamics simulation molecular docking