Creative Biolabs is a leading chemical proteomics company offering high-quality services for target deconvolution. We have cutting-edge chemical proteomics technologies that can be used in biomarker research, drug and target discovery, pathway modeling, mechanisms of action studies, and many other areas, which enable us to provide superior, comprehensive services for target deconvolution to meet customers' various needs.

Chemical proteomics is a rapidly evolving area of chemical biology that seeks to design small molecule probes to understand small molecule mode of action and protein function in drug discovery. It can be used to identify the protein binding partners or targets of small molecules in live cells. Chemical proteomics offers a range of novel methodologies for target deconvolution, the discovery of drug response biomarkers and disease pathway analysis for preclinical target validation. A variety of methods can be employed in the chemical proteomics workflow. At Creative Biolabs, we provide multiple methods for the identification and validation of novel drug targets, some of which are listed below.

Affinity-chromatography-based methods for target deconvolution.Fig.1 Affinity-chromatography-based methods for target deconvolution.
(Terstappen, 2007)

Affinity chromatography is the most widely used method for isolating specific target proteins from complex proteomes (Fig.1). In this method, small molecules are immobilized onto solid support that can be used to separate bound protein targets. The unbound proteins are removed by a washing step followed by a specific method to elute the protein of interest. The eluted protein can be identified using "shotgun" type sequencing methods with multi-dimensional liquid chromatography or be further separated by SDS-PAGE and analyzed by mass spectrometry (MS). The identified peptide sequences can then be used in a database search to identify the target protein.

Pal is a powerful technology for drug discovery that can be used to identify new drug targets and molecular interactions as well as to probe the location and structure of binding sites. Pal probe is a derivative of a drug with two functional groups: a photo-crosslinked group that forms a covalent bond under ultraviolet (UV) irradiation and a purification tag group. In this method, live cells or protein mixtures are incubated with the derivatized compound, and the compound-protein binding then fixed by UV irradiation. The protein covalently bound to the compound derivative is then purified by affinity tag and subjected to MS-based proteomics to identify the protein.

Abpp utilizes active site-directed chemical probes to analyze the functional state of enzymes in crude biological samples. The activity-based probe has at least two components: a reactive group for covalently binding to the active site of the enzyme and a reporter group for detecting and enriching the probe-labeled enzyme. At present, ABPP probes for several enzyme classes have been developed, including proteases, serine hydrolases, phosphatases, kinases, glycosidases, oxidoreductases, and methyltransferases. If a suitable ABPP probe is available, the Abpp used for the target deconvolution does not require any derivatization of the compound. Therefore, this method can quickly and systematically identify target proteins in the entire proteome.

Drug affinity responsive target stability (DARTS)<br> for target deconvolution.Fig.3 Drug affinity responsive target stability (Darts)
for target deconvolution. (Lomenick, 2009)

Darts is a relatively rapid and straightforward method for identifying potential protein targets for small molecules. It relies on proteolytic protection conferred to the target protein by interaction with small molecules. Darts is performed by simply treating an aliquot of cell lysate with the target compound and vehicle control or inactive analog, followed by limited digestion of the protein in the cell lysate with protease (Fig.3). Subsequently, samples are separated by SDS-PAGE and stained to identify protein bands that are protected from proteolysis by small molecules. The MS is then used to identify the proteins present in each band. Nowadays, Darts has been successfully used to identify novel protein targets for natural products and other bioactive small molecules.

Features

  • Work on reliable interactions
  • Save time on the analysis of your screen results
  • Speed up your functional validation
  • Accelerate the process of discovering new, high quality and available drug targets

At Creative Biolabs, we provide our global customers with high-quality chemical proteomics services, including but not limited to the above, and comprehensive solutions to accelerate their drug discovery process. With our comprehensive solutions, you won't waste money and time on the wrong candidates and you'll be able to optimize the success rate of your drug development and drug discovery program. For more information, please contact us directly.

References

    1. Terstappen, G. C.; et al. Target deconvolution strategies in drug discovery. Nature Reviews Drug Discovery. 2007, 6(11): 891.
    2. Kubota, K.; et al. Target deconvolution from phenotype-based drug discovery by using chemical proteomics approaches. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 2019, 1867(1): 22-27.
    3. Lomenick, B.; et al. Target identification using drug affinity responsive target stability (DARTS). Proceedings of the National Academy of Sciences. 2009, 106(51): 21984-21989.

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