Structure-based discovery of potassium channel blockers from natural products: virtual screening and electrophysiological assay testing.
Potassium ion (K(+)) channels are attractive targets for rational drug design. Based upon a three-dimensional model of the eukaryotic K(+) channels, the docking virtual screening approach was employed to search the China Natural Products Database. Compounds were ranked according to the relative binding energy, favorable shape complementarity, and potential of forming hydrogen bonds with the K(+) channel. Four candidate compounds found by virtual screening were investigated by using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. When applied extracellularly, compound 1 markedly depressed the delayed rectifier K(+) current (I(K)) and fast transient K(+) current (I(A)), whereas compounds 2, 3, and 4 exerted a more potent and selective inhibitory effect on I(K). Intracellular application of the four compounds had no effect on both the K(+) currents.
Liu
Hong
H
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 201203, Shanghai, People's Republic of China.
Li
Yang
Y
Song
Mingke
M
Tan
Xiaojian
X
Cheng
Feng
F
Zheng
Suxin
S
Shen
Jianhua
J
Luo
Xiaomin
X
Ji
Ruyun
R
Yue
Jianmin
J
Hu
Guoyuan
G
Jiang
Hualiang
H
Chen
Kaixian
K
D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015221:Potassium Channels; D051381:Rats; D013329:Structure-Activity Relationship
D001688:Biological Products; D026902:Potassium Channel Blockers; D015221:Potassium Channels