Small-molecule chemical libraries

Although the peptide aminomethylcoumarin (AMC) substrate approach has been widely used for measuring the activities of many proteases, a disadvantage of this approach arises from the ultraviolet excitation and emission wavelengths required for detecting free AMC where there is a possibility for fluorescence interference. RllO-labeled substrates are less encumbered by interference due to a spectral red shift, but many compounds in small molecule chemical libraries exhibit fluorescent properties that may interfere with assays based on fluorescence detection (Simenov et al. 2008). 

Thorpe, D.S., Chan, A. W. E., Binnie, A., et al. (1999) Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules. Biochem. Biophys. ReS. Commun. 266 62-65. 

Precisely defined collections of different chemical compounds are denominated as chemical libraries that can be efficiently prepared by methods of combinatorial chemistry. Each chemical compound owes specific structural, steiic, and electronic properties that determine all possible interactions of the small molecule with a given protein or receptor. The molecule s properties are based on the steiic arrangement of functional groups, including the conformations that can be attained by a specific structure. 

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

Tietze, L.F. Lieb, M.E. (1998) Domino Reactions for Library Synthesis of Small Molecules in Combinatorial Chemistry. Current Opinion in Chemical Biology, 2, 363-371. 

The application of forward chemical genetics to studies of translation provides an opportunity to identify small molecules that inhibit or stimulate this process without any underlying assumptions as to which step is most amenable to targeting by the chemical libraries under consideration. The opportunity exists to identify novel factors involved in translation, unravel new activities of known translation initiation factors, or characterize shortlived intermediates that are frozen by the small molecule inhibitor. We have undertaken a forward chemical genetic approach to identify small molecules that inhibit or stimulate translation in extracts prepared from Krebs-2 ascites cells (Novae et al., 2004). These screens have led to the identification of several novel inhibitors of translation initiation and elongation (Bordeleau et al., 2005, 2006 Robert et al., 2006a,b). 

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