Modeling of alphak/gamma2 (k=1, 2, 3 and 5) interface of GABA A receptor and docking studies with zolpidem: implications for selectivity.
The three-dimensional models of the alphak/gamma2 (k=1, 2, 3 and 5) interface of GABA(A) receptors, which included the agonist-binding site, were constructed and validated by molecular modeling technology. To investigate the mechanism of alpha subunit selectivity of zolpidem, docking calculations were used to illustrate the potential binding modes of zolpidem with different alpha subtypes. The results revealed that there were three reasons resulting in the distinct binding affinity of zolpidem to different alpha subtype. Firstly, the number of hydrogen bonds of agonist-receptor complex would determine the magnitude of binding affinity. Secondly, the His residue in loop A of alpha subunit was indicated as a key role of benzodiazepine binding. Thirdly, the side chain of Glu in loop C reduced the affinity of zolpidem to those receptors containing alpha2, alpha3 or alpha5 subunits.
Ci
Su-Qin
SQ
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100080, China.
Ren
Tian-Rui
TR
Ma
Cai-Xia
CX
Su
Zhi-Guo
ZG
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D019281:Dimerization; D018755:GABA Agonists / Q000737:chemistry / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000077334:Zolpidem
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem