Lee William, Mann Stefan A, Windley Monique J, Imtiaz Mohammad S, Vandenberg Jamie I, Hill Adam P
Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, University of New South Wales, NSW 2052, Australia.
Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia.
Prog Biophys Mol Biol. 2016 Jan;120(1-3):89-99. doi: 10.1016/j.pbiomolbio.2015.12.005. Epub 2015 Dec 20.
The Kv11.1 or hERG potassium channel is responsible for one of the major repolarising currents (IKr) in cardiac myocytes. Drug binding to hERG can result in reduction in IKr, action potential prolongation, acquired long QT syndrome and fatal cardiac arrhythmias. The current guidelines for pre-clinical assessment of drugs in development is based on the measurement of the drug concentration that causes 50% current block, i.e., IC50. However, drugs with the same apparent IC50 may have very different kinetics of binding and unbinding, as well as different affinities for the open and inactivated states of Kv11.1. Therefore, IC50 measurements may not reflect the true risk of drug induced arrhythmias. Here we have used an in silico approach to test the hypothesis that drug binding kinetics and differences in state-dependent affinity will influence the extent of cardiac action potential prolongation independent of apparent IC50 values. We found, in general that drugs with faster overall kinetics and drugs with higher affinity for the open state relative to the inactivated state cause more action potential prolongation. These characteristics of drug-hERG interaction are likely to be more arrhythmogenic but cannot be predicted by IC50 measurement alone. Our results suggest that the pre-clinical assessment of Kv11.1-drug interactions should include descriptions of the kinetics and state dependence of drug binding. Further, incorporation of this information into sophisticated in silico models should be able to better predict arrhythmia risk and therefore more accurately assess safety of new drugs in development.
Kv11.1或hERG钾通道负责心肌细胞中主要的复极化电流之一（IKr）。药物与hERG结合会导致IKr降低、动作电位延长、获得性长QT综合征和致命性心律失常。目前用于评估正在研发药物的临床前指南是基于对引起50%电流阻滞的药物浓度的测量，即IC50。然而，具有相同表观IC50的药物可能具有非常不同的结合和解离动力学，以及对Kv11.1开放和失活状态的不同亲和力。因此，IC50测量可能无法反映药物诱发心律失常的真正风险。在这里，我们使用了一种计算机模拟方法来检验以下假设：药物结合动力学和状态依赖性亲和力的差异将独立于表观IC50值影响心脏动作电位延长的程度。我们发现，一般来说，整体动力学较快的药物以及相对于失活状态对开放状态具有更高亲和力的药物会导致更多的动作电位延长。药物与hERG相互作用的这些特征可能更具致心律失常性，但不能仅通过IC50测量来预测。我们的结果表明，Kv11.1-药物相互作用的临床前评估应包括药物结合动力学和状态依赖性的描述。此外，将这些信息纳入复杂 的计算机模拟模型应该能够更好地预测心律失常风险，从而更准确地评估正在研发的新药的安全性。
