An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment
An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment
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DOI：
10.1152/ajpheart.00808.2011
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发表时间：
2012-04-01
影响因子：
4.8
通讯作者：
Abi-Gerges, N.
中科院分区：
文献类型：
--
作者：
Davies, M. R.;Mistry, H. B.;Abi-Gerges, N.
Davies MR, Mistry HB, Hussein L, Pollard CE, Valentin JP, Swinton J, Abi-Gerges N.一种用于早期药物安全性评估的犬心脏心肌中期动作电位持续时间模型。[J]中国生物医学工程学报，2012,31(2):444 - 444。首次发表于2011年12月23日；doi: 10.1152 / ajpheart.00808.2011。表达离子通道（IC）的细胞系和基于平板的电生理装置的出现，使得对动作电位（AP）的分子理解成为早期QT评估的一种手段。我们试图开发一种硅AP （isAP）模型，该模型使用来自五个ic （hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1）的浓度-效应曲线数据来评估化合物对心肌细胞AP持续时间（APD）的影响。一组53种化合物被选择来覆盖一系列选择性和混合IC调制器，测试它们对光学测量APD的影响。在90%复极时，APD变化阈值为> - 10% （APD(90)）表示最高测试浓度的影响。为了捕获19只不同狗左心室心肌中肌细胞APD数据的变化，isAP模型被校准以产生19个模型变体的集合，这些模型变体可以捕获APs的形状和形式，并定量地复制多非利特和地尔硫卓诱导的APD90变化。仅提供IC面板数据，然后使用isAP模型，盲法预测APD（90）变化大于10%。在模拟浓度为30 μ M时，基于6个变体必须同意的标准，isAP预测得分为显示大于80%的化合物活性预测。因此，在药物发现的早期，isAP模型允许集成单独的IC数据，并适应作为虚拟屏幕使用所需的吞吐量。
Davies MR, Mistry HB, Hussein L, Pollard CE, Valentin JP, Swinton J, Abi-Gerges N. An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. Am J Physiol Heart Circ Physiol 302: H1466-H1480, 2012. First published December 23, 2011; doi: 10.1152/ajpheart.00808.2011.-Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide-and diltiazem-induced APD90 changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 mu M and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.