title: Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.
abstract: Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.
authors.affiliation: 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, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Zhao-Bing
authors.initials: ZB
authors.lastname: Gao
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yao
authors.forename: Suxin
authors.initials: S
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Tan
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Hu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004147:Dioxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006624:Hippocampus / Q000166:cytology; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D004147:Dioxins; D009281:Naphthalenes; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051637:Shaker Superfamily of Potassium Channels; D013450:Sulfones