Insights into the suanzaoren mechanism-From constructing the 3D structure of GABA-A receptor to its binding interaction analysis

Gamma aminobutyric acid type A (GABA-A) receptors are an important therapeutic target in insomnia treatment. The GABA-A protein structure is still not available. In this study, a reliable structure of GABA-A receptor was built and validated by several criteria. Zolpidem was predicted to gain the highest binding affinity at the BZ-binding site and be surrounded by alpha(1)-His129, alpha(1)-Try-187, alpha(1)-Gly228, alpha(1)-Thr234, alpha(1)-Tyr237, gamma(2)-Met96. gamma(2)-Phe 116, and gamma(2)-Met 169. In addition, GABA formed five hydrogen bonds with alpha(1)-Arg 159, beta(2)-Glu 179, and beta(2)-Tyr 181 and was surrounded by the residues alpha(1)-Phe92, alpha(1)-Arg 147, beta(2)-Tyr181, beta(2)-Thr 184, beta(2)-Thr 226, and beta(2)-Tyr229 at the GABA-binding site, The two simulation results were consistent with the experimental assay, which suggested that the simulated GABA-A receptor was reliable. Jujuboside A. which was considered the effective suanzaoren constituent, had difficulty penetrating the blood-brain barrier, Besides, jujuboside A was unable to bind at both binding sites due to its large structural volume. However, jujubogenin that was hydrolyzed from jujuboside A showed the most compatible binding pose and formed five hydrogen bonds with the key residues, beta(2)-Thr226 and beta(2)-Tyr-229, at the GABA-binding site. In addition, according to a docking study, jujubogenin gained higher scoring values, which indicated a higher binding affinity. Moreover, the adsorption, distribution, metabolism, excretion, and toxicity (ADMET) descriptors predicted that jujubogenin had high blood-brain barrier penetration. Conclusively, jujubogenin was suggested to be the effective suanzaoren constituent for exerting the sedative function via GABA-A receptor. (C), 2008 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.