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 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 (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 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 (α₁) to the center of mass of the ligands. The results reveal that the distance between the C(α) 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 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 (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 GABA(A)R-ligand interactions and helps to arrive at a binding mode hypothesis with implications for drug design.
Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Hong-Bo
HB
Xie
Yu
Y
Sha
Jian
J
Wang
Mao-Sheng
MS
Cheng
D000595:Amino Acid Sequence; D053961:Azabicyclo Compounds / Q000737:chemistry; D001665:Binding Sites; D000069582:Eszopiclone; D005479:Flurazepam / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D005479:Flurazepam; D000069582:Eszopiclone