Chemical libraries, characterization

Chemoinformatics (or cheminformatics) deals with the storage, retrieval, and analysis of chemical and biological data. Specifically, it involves the development and application of software systems for the management of combinatorial chemical projects, rational design of chemical libraries, and analysis of the obtained chemical and biological data. The major research topics of chemoinformatics involve QSAR and diversity analysis. The researchers should address several important issues. First, chemical structures should be characterized by calculable molecular descriptors that provide quantitative representation of chemical structures. Second, special measures should be developed on the basis of these descriptors in order to quantify structural similarities between pairs of molecules. Finally, adequate computational methods should be established for the efficient sampling of the huge combinatorial structural space of chemical libraries. 

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). 

Nedved, M. L. Habibi-Goudarzi, S. Ganem, B. Henion, J. D. 1996. Characterization of benzodiazepine combinatorial chemical libraries by on-line immunoaffinity extraction, coupled column HPLC-ion spray mass spectrometry-tandem mass spectrometry. Anal. Chem., 68, 4228-4236. 

Auld, D.S. et al. 2008. Characterization of chemical libraries for luciferase inhibitory activity. J. Med. Chem. 51, 2372-2386. 

M.L. Nedved, S. Habibi-Goudarzi, B. Ganem, J.D. Henion, Characterization of benzodiazepine combinatorial" chemical libraries by on-line lAC, coupled column LC-ESI-MS-MS, Anal. Chem., 68 (1996) 4228. 

Combinatorial approaches make it relatively straightforward to generate chemical libraries with vast number of new compounds thus synthesis is often no longer the rate-limiting step in drug discovery. Since almost all analytical characterization tools are serial techniques, the purification and analysis of the chemical libraries has instead become a new bottleneck. This, of course, imposes new analytical challenges in the fields associated with... 

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