Small molecules screening systems

Metz G, Ottleben H, Vetter D. Small molecule screening on chemical microarrays. Meth. Princ. Med. Chem. 2003 19 213-236. Ladame S. Dynamic combinatorial chemistry on the road to fulfilling the promise. Org. Biomol. Chem. 2008 6 219-226. Hioki H, Still WC. Chemical evolution a model System that selects and amplifies a receptor for the tripeptide D-Pro-L-Val-D-Val. J. Org. Chem. 1998 63 904-905. 

The Xenopus laevis egg extract system overcomes some of the limitations of using purified proteins or cells/organisms for small-molecule screening by providing a cell-free, yet robust, biologically active system that can be readily manipulated [1]. 

The development of protein chip assays to determine protein function using purified components is a rapidly advancing area. Automated systems for the assay of protein function on chips in parallel for thousands of proteins simultaneously will likely be available in the next few years. These miniaturized arrays will be useful for basic research as well as for diagnostics and drug development. For instance, the combination of protein chips with combinatorial chemistry will allow the simultaneous screening of vast collections of small molecules against vast collections of potential target proteins. 

Consider one small molecule, phenylalanine. It is an essential amino acid in our diet and is important in protein synthesis (a component of protein), as well as a precursor to tyrosine and neurotransmitters. Phenylalanine is one of several amino acids that are measured in a variety of clinical methods, which include immunoassay, fluorometry, high performance liquid chromatography (HPLC see Section 4.1.2) and most recently MS/MS (see Chapter 3). Historically, screening labs utilized immunoassays or fluorimetric analysis. Diagnostic metabolic labs used the amino acid analyzer, which was a form of HPLC. Most recently, the tandem mass spectrometer has been used extensively in screening labs to analyze amino acids or in diagnostic labs as a universal detector for GC and LC techniques. Why did MS/MS replace older technological systems The answer to this question lies in the power of mass spectrometer. 

The fast growing amount of molecular information related to small molecule interactions with biological systems, generated in both academic and industrial screening centers, requires the design of molecular information systems which integrate bio- and chemoinformatics... 

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