Chemical proteomics-based analysis of off-target binding profiles for rosiglitazone and pioglitazone: clues for assessing potential for cardiotoxicity.
Chemical proteomics-based analysis of off-target binding profiles for rosiglitazone and pioglitazone: clues for assessing potential for cardiotoxicity.
复制标题
DOI：
10.1021/jm301204r
复制
发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Greene, Andrew S.
中科院分区：
文献类型：
--
作者：
Hoffimann, Brian R.;El-Mansy, Mohamed F.;Sem, Daniel S.;Greene, Andrew S.
药物通常通过与蛋白质靶标(S)和靶外蛋白质(S)的结合而发挥预期和不良的生物效应，为药物的疗效和毒性提供了证据。吡格列酮和罗格列酮有一个共同的功能核心，格列酮，它被认为是一个特权的支架，在此基础上建立针对特定靶点的药物选择性--在这种情况下是PPARγ。在此，我们报告了对格列酮支架的两种变体，吡格列酮和罗格列酮的回顾分析，以努力确定大鼠心脏中的靶外结合事件，以解释最近报道的与药物相关的心血管风险。我们的结果表明格列酮对脱氢酶有亲和力，与已知的对相关罗丹宁核心的结合偏好一致。这两种药物都结合了离子通道和调节剂，与充血性心力衰竭、心律失常和外周水肿有关。还检测到与葡萄糖稳态、突触转导和线粒体能量产生有关的其他蛋白质，这些蛋白质可能与药物疗效和心脏毒性有关。
Drugs typically exert desired and undesired biological effects by virtue of binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target – in this case PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with the drugs. Our results suggest glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity.
登录
查看更多内容
影响因子：
3.1
作者：
Heppner, TJ;Bonev, AD;Nelson, MT
通讯作者：
Nelson, MT
影响因子：
2.9
作者：
Gutschi, L. Maria;Malcolm, Janine C.;Ooi, Teik Chye
通讯作者：
Ooi, Teik Chye
影响因子：
5
作者：
Knock, GA;Mishra, SK;Aaronson, PI
通讯作者：
Aaronson, PI
影响因子：
4.8
作者：
Dello Russo, C;Gavrilyuk, V;Feinstein, DL
通讯作者：
Feinstein, DL
影响因子：
3.4
作者：
Halligan, Brian D.;Greene, Andrew S.
通讯作者：
Greene, Andrew S.