Gaining Insight into Off-Target Mediated Effects of Drug Candidates with a Comprehensive Systems Chemical Biology Analysis

被引：112

作者：

Scheiber, Josef ^{[1
]}

Chen, Bin ^{[1
]}

Milik, Mariusz ^{[1
]}

Sukuru, Sai Chetan K. ^{[1
]}

Bender, Andreas ^{[1
]}

Mikhailov, Dmitri ^{[1
]}

Whitebread, Steven ^{[2
]}

Hamon, Jacques ^{[3
]}

Azzaoui, Kamal ^{[4
]}

Urban, Laszlo ^{[2
]}

Glick, Meir ^{[1
]}

Davies, John W. ^{[1
]}

Jenkins, Jeremy L. ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, CPC, Lead Discovery Informat, Cambridge, MA 02139 USA

[2] Novartis Inst Biomed Res, CPC, Preclin Safety Profiling, Cambridge, MA 02139 USA

[3] Novartis Pharma AG, CPC, Preclin Safety Profiling, CH-4002 Basel, Switzerland

[4] Novartis Pharma AG, CPC, Mol Lib Informat, CH-4002 Basel, Switzerland

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2009年 / 49卷 / 02期

关键词：

QT INTERVAL PROLONGATION; HIGH-THROUGHPUT DOCKING; MOLECULAR DESCRIPTORS; STATIN MYOPATHY; SKELETAL-MUSCLE; RHABDOMYOLYSIS; PHARMACOPHORE; MICE; PHARMACOLOGY; NETWORK;

D O I：

10.1021/ci800344p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We present a workflow that leverages data from chemogenomics based target predictions with Systems Biology databases to better understand off-target related toxicities. By analyzing a set of compounds that share a common toxic phenotype and by comparing the pathways they affect with pathways modulated by nontoxic compounds we are able to establish links between pathways and particular adverse effects. We further link these predictive results with literature data in order to explain why a certain pathway is predicted. Specifically, relevant pathways are elucidated for the side effects rhabdomyolysis and hypotension. Prospectively, our approach is valuable not only to better understand toxicities of novel compounds early on but also for drug repurposing exercises to find novel uses for known drugs.

引用

页码：308 / 317

页数：10

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