Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.
Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
Sci Rep. 2019 Nov 12;9(1):16586. doi: 10.1038/s41598-019-53120-6.
The human ether-a-go-go-related gene (hERG) encodes a voltage-gated potassium channel that plays an essential role in the repolarization of action potentials in cardiac muscle. However, various drugs can block the ion current by binding to the hERG channel, resulting in potentially lethal cardiac arrhythmia. Accordingly, in silico studies are necessary to clarify the mechanisms of how these drugs bind to the hERG channel. Here, we used the experimental structure of the hERG channel, determined by cryo-electron microscopy, to perform docking simulations to predict the complex structures that occur between the hERG channel and structurally diverse drugs. The absolute binding free energies for the models were calculated using the MP-CAFEE method; calculated values were well correlated with experimental ones. By applying the regression equation obtained here, the affinity of a drug for the hERG channel can be accurately predicted from the calculated value of the absolute binding free energy.
人类 ether-a-go-go 相关基因（hERG）编码一种电压门控钾通道，在心肌动作电位复极化中发挥着重要作用。然而，各种药物可以通过与 hERG 通道结合来阻断离子电流，从而导致潜在的致命性心律失常。因此，有必要进行计算机模拟研究来阐明这些药物与 hERG 通道结合的机制。在这里，我们使用低温电子显微镜测定的 hERG 通道的实验结构来进行对接模拟，以预测 hERG 通道和结构多样的药物之间发生的复杂结构。使用 MP-CAFEE 方法计算模型的绝对结合自由能；计算值与实验值很好地相关。通过应用这里得到的回归方程，可以根据绝对结合自由能的计算值准确预测药物对 hERG 通道的亲和力。
