Target deconvolution

Small molecule carbohydrates, lipids, natural products, drugs, drug-like molecules synthesis platform, ligand discovery, antibody binding screens, enzymatic assays, phenotypic cell-based screens, diagnostics, target deconvolution 12, 14-16, 21, 22, 25-32, 39, 40, 43, 44, 46, 48, 53, 55-65, 78... 

Protein antibodies, peptides, protein domains, functional proteins, clarified cell lysates enzymatic assays, mapping protein-DNA interactions, mapping protein-protein interactions, mapping post-translational modifications, target deconvolution, antibody, binding screens, protein expression profiling and biomarker discovery 13, 17, 23, 33-35, 37, 38, 41, 42, 45, 47, 66-75... 

Saxena, C., Zhen, E., Higgs, R.E., and Hale, J.E. (2008) An immuno-chemo-pro-teomics method for drug target deconvolution. J. Proteome Res. 7, 3490-3497. 

U.H., and Bender, A. (2009) Fishing the target of antituhercular compounds in silico target deconvolution model development and validation. Journal of Proteome Research, 8, 2788—2798. 

Terstappen, G.C. et al. Target deconvolution strategies in drug discovery. Nature Rev. Drug Discov. 2007, 6, 891-903. 

Figure 1.20 The major elements of the pull-down assay. (From Terstappen, G. C. et al., 2007, Target Deconvolution Strategies in Drug Discovery, Nat. Rev. Drug Disc., 6 891-903.)...

The synthesis of the natural-product-inspired indoloquinolizine compound collection, the HCS for mitotic inhibitors and the elucidation of the mode of action of centrocountin 1 is a demonstrative example of the forward-chemical genetics approach. It illustrates the workflow for the identification of biologically active small molecules in cells and target deconvolution. Centrocountin 1 was the most potent hit compound in a screen for mitotic inhibition and impairs the proper chromosome congression in cells. This results in chromosomal misalignment and... 

From a medicinal chemistry perspective, the optimization of a lead series for affinity, selectivity, and pharmacological profile is often more intuitive if the efficacy target(s) is known. This suggests that MMoA elucidation (i.e., the so-called target deconvolution or deorphaning) of the hits or leads derived from phenotypic screens can be useful both in their further development and for finding additional chemical series. 

Two different types of in silico analysis are relevant for in silica target deconvolution (i) correlation analysis between phenotypic screening results and the in vitro biochemical profile of the screened compounds and (ii) machine learning models to predict the targets for the hits in the phenotypic screening. Two independent studies have been published very recently where the Fisher exact test... 

An important drawback of all knowledge-based approaches to target deconvolution is that they are only applicable to identify targets for which there are already known small-molecule modulators, with a reasonable amoimt of in vitro bioactivity data available, thus completely new targets cannot be predicted. Another issue is that if the compounds are active against two or more... 

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