Some insights into the binding mechanism of the GABAA receptor: a combined docking and MM-GBSA study
Gamma-aminobutyric type A receptor (GABAAR) 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 2α12β2γ2 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 (α1), Phe77 (γ2) and Phe100 (α1) 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 Cα of the mutant residue His102A (α1) to the center of mass of the ligands.The results reveal that the distance between the Cα of the mutant residue His102A (α1) to the center of flurazepam is larger than that between His102 (α1) to flurazepam in the WT type complex.Molecular mechanicgeneralized 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 (R2-0.87) with the experimental binding free energies.Overall, the major interaction comes from a few groups around His102 (α1), Phe77 (γ2) and Phe100 (α1).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 GABAAR-ligand interactions and helps to arrive at a binding mode hypothesis with implications for drug design.
Gamma-aminobutyric acid type A receptors Homology modeling Molecular dynamics simulation Molecular docking Molecular mechanic-generalized Born surface area
Hong-Bo Xie Yu Sha Jian Wang Mao-Sheng Cheng
Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pha Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pha
国内会议
苏州
英文
347-358
2014-10-26（万方平台首次上网日期，不代表论文的发表时间）