Possible drug candidates for Alzheimer's disease deduced from studying their binding interactions with alpha7 nicotinic acetylcholine receptor.
Dysfunction in alpha7 nicotinic acetylcholine receptor (nAChR), a member of the Cys-loop ligand-gated ion channel superfamily, is responsible for attentional and cognitive deficits in Alzheimer's disease (AD). To provide useful information for finding drug candidates for the treatment of AD, a study was carried out according to the following procedures. (1) DMXBA, a partial agonist of the alpha7 nAChR, was used as a template molecule. (2) To reduce the number of compounds to be considered, the similarity search and flexible alignment were conducted to exclude those molecules which did not match the template. (3) The molecules thus obtained were docked to alpha7 nAChR. (4) To gain more structural information, the molecular dynamics (MD) simulations were carried out for 9 most favorable agonists obtained by the aforementioned docking studies. (5) By analyzing the hydrogen bond interaction and hydrophobic/hydrophilic interaction, the following seven compounds were singled out as possible drug candidates for AD therapy: gx-50, gx-51, gx-52, gx-180, open3d-99008, open3d-51265, open3d-60247.
Gu
Ruo-Xu
RX
College of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China.
Gu
Hui
H
Xie
Zhi-Yuan
ZY
Wang
Jing-Fang
JF
Arias
Hugo R
HR
Wei
Dong-Qing
DQ
Chou
Kuo-Chen
KC
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine