赫尔格
药效团
对接(动物)
化学
虚拟筛选
药物发现
生物信息学
结合位点
钾通道
计算生物学
小分子
药理学
立体化学
生物物理学
生物化学
生物
基因
医学
护理部
作者
Callum J. Dickson,Camilo Velez-Vega,José S. Duca
标识
DOI:10.1021/acs.jcim.9b00773
摘要
The Kv11.1 potassium channel, encoded by the human ether-a-go-go-related gene (hERG), plays an essential role in the cardiac action potential. hERG blockade by small molecules can induce “torsade de pointes” arrhythmias and sudden death; as such, it is an important off-target to avoid during drug discovery. Recently, a cryo-EM structure of the open channel state of hERG was reported, opening the door to in silico docking analyses and interpretation of hERG structure–activity relationships, with a view to avoiding blocking activity. Despite this, docking directly to this cryo-EM structure has been reported to yield binding modes that are unable to explain known mutagenesis data. In this work, we use molecular dynamics simulations to sample a range of channel conformations and run ensemble docking campaigns at the known hERG binding site below the selectivity filter, composed of the central cavity and the four deep hydrophobic pockets. We identify a hERG conformational state allowing discrimination of blockers vs nonblockers from docking; furthermore, the binding pocket agrees with mutagenesis data, and blocker binding modes fit the hERG blocker pharmacophore. We then use the same protocol to identify a binding pocket in the hERG channel pore for hERG activators, again agreeing with the reported mutagenesis. Our approach may be useful in drug discovery campaigns to prioritize candidate compounds based on hERG liability via virtual docking screens.
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