Target Fishing by Cross‐Docking to Explain Polypharmacological Effects
Target Fishing by Cross‐Docking to Explain Polypharmacological Effects
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DOI：
10.1002/cmdc.201500123
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发表时间：
2015-07
期刊：
影响因子：
3.4
通讯作者：
Hitesh Patel;X. Lucas;I. Bendik;S. Günther;I. Merfort
中科院分区：
文献类型：
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作者：
Hitesh Patel;X. Lucas;I. Bendik;S. Günther;I. Merfort
药物可能具有多药理现象，即除了期望的靶点外，还可能结合许多不希望的或未知的生理靶点。因此，它们经常产生副作用。在某些情况下，脱靶相互作用可能导致药物重新定位或解释药物的作用模式。在这里，我们提出了一种通过交叉对接的目标捕捞的计算机方法，作为鉴定新的药物-蛋白质相互作用的方法。作为一个例子和概念证明，该方法预测了过氧化物酶体增殖物激活受体(PPAR) γ作为乙炔酸的靶标，这可能解释了该分子带来的高血糖效应。乙酸对PPAR‐γ的拮抗作用在人HEK293细胞的瞬时反激活实验中得到了验证。交叉对接方法还预测了许多其他药物副作用的潜在机制，并揭示了新的药物重新定位机会。本文描述了这些假定的相互作用，并且可以很容易地用于发现治疗相关的药物作用。
Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off‐target interactions may lead to drug repositioning or to explaining a drug’s mode of action. Herein we present an in silico approach for target fishing by cross‐docking as a method to identify new drug–protein interactions. As an example and proof of concept, this method predicted the peroxisome proliferator‐activated receptor (PPAR)‐γ as a target of ethacrynic acid, which may explain the hyperglycemic effect brought on by this molecule. The antagonistic effect of ethacrynic acid on PPAR‐γ was validated in a transient transactivation assay using human HEK293 cells. The cross‐docking approach also predicted the potential mechanisms of many other drug side effects and discloses new drug repositioning opportunities. These putative interactions are described herein, and can be readily used to discover therapeutically relevant drug effects.