Target Identification Using Drug Affinity Responsive Target Stability (DARTS)

Lomenick, Brett; Jung, Gwanghyun; Wohlschlegel, James A.; Huang, Jing

doi:10.1002/9780470559277.ch110180

Cited by 221 publications

(241 citation statements)

References 14 publications

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“…The Drug Affinity Responsive Target Stability (DARTS) assay was optimized and used to assess the binding of SC144 on MDA-7/IL-24 via the protease protection from pronase (Roche Applied Science, Inc.) as previously described [43,44]. HCT116 p53+/+ cells were lysed using M-PER (Thermo Scientific, Inc.) supplemented with protease inhibitors and phosphatase inhibitors.…”

Section: Darts Assaymentioning

confidence: 99%

Stabilization of MDA-7/IL-24 for colon cancer therapy

Oshima

Imada

et al. 2013

Cancer Letters

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Section: Darts Assaymentioning

confidence: 99%

Stabilization of MDA-7/IL-24 for colon cancer therapy

Oshima

Imada

et al. 2013

Cancer Letters

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“…Huang and coworkers developed a label-free method named drug affinity responsive target stability (DARTS, Fig. 2c), (Pai et al 2015) which utilizes the higher resistance of proteins to proteolysis after ligand binding (Lomenick et al 2009(Lomenick et al , 2011a. In a recent example, DARTS successfully identified the target of a-ketoglutarate, a tricarboxylic acid cycle intermediate which can extend the lifespan of adult Caenorhabditis elegans; this study revealed new roles of a common metabolite in the regulation of organismal lifespan (Chin et al 2014).…”

Section: Probe Modification and Label-free Probes In Affinity Purificmentioning

confidence: 94%

Affinity purification in target identification: the specificity challenge

Zheng

2015

Arch. Pharm. Res.

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Since phenotype-based screening directly evaluates capability of small molecules for modulating biology in actual biological systems, it has become an important discover modality in modern pharmaceutical sciences. However, in order to fully elucidate the molecular mechanism underlying the bioactivity of small molecules, identification of their biological targets is an indispensable step. Among the many target identification strategies developed during the past several decades, affinity purification remains to be one of the most important and powerful approaches, as it can directly reveal the physical interactions between small molecules and their biomolecular targets. However, due to the complexity of the proteome and the diversity of small molecule-protein interactions, affinity purification faces the specificity challenge: how to identify the true specific targets from the non-specific background? Focusing on this challenge, in this review, we briefly introduce the history and background of affinity purification, and then we discussed the major technological developments aiming to address this challenge. We have summarized these approaches in two categories: noise reduction and comparative distinction. This review also highlights the importance of choosing an integrated approach combining multiple methods to achieving success in target identification.

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“…The ratio of peak intensities in the mass spectrum reflects the abundance ratio for the proteins. Another technique called drug affinity responsive target stability (DARTS) is based on the principle that drug-target binding can form a more stable complex relative to a bare protein (Lomenick et al, 2009). Briefly, cell lysate is incubated with drug molecules and vehicles, and the subsequent proteolysis process will degrade most proteins except the chemical-linked complex, which is then visualized on gel bands.…”

Section: The Concept Of the Chemical-protein Interactomementioning

confidence: 99%

Chemical-protein interactome and its application in off-target identification

Yang

Wang

et al. 2011

Interdiscip Sci Comput Life Sci

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Drugs exert their therapeutic and adverse effects by interacting with molecular targets. Although designed to interact with specific targets in a desirable manner, drug molecules often bind to unexpected proteins (off-targets). By activating or inhibiting off-targets and the associated biological processes and pathways, the resulting chemical-protein interactions can influence drug reaction directly or indirectly. Exploring the relationship between drug and off-targets and the downstream drug reaction can help understand the polypharmacology of the drug, hence significantly advance the drug repositioning pipeline and the application of personalized medicine in understanding and preventing adverse drug reaction. This review summarizes works on predicting off-targets via chemical-protein interactome (CPI), an interaction strength matrix of drugs across multiple human proteins aiming at exploring the unexpected drug-protein interactions, with a variety of computational strategies, including docking, chemical structure comparison and text-mining etc. Effective recall on previous knowledge, de novo prediction and subsequent experimental validation conferred us strong confidence in these methods. Such studies present prospect of large scale in silico methodologies for off-target discovery with low cost and high efficiency.

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Target Identification Using Drug Affinity Responsive Target Stability (DARTS)

Cited by 221 publications

References 14 publications

Stabilization of MDA-7/IL-24 for colon cancer therapy

Stabilization of MDA-7/IL-24 for colon cancer therapy

Affinity purification in target identification: the specificity challenge

Chemical-protein interactome and its application in off-target identification

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