Discovery of Small Molecule Probes

In this section, the discovery of small molecules for the interrogation of biological mechanisms will be described. An appropriate small molecule tool may be discovered either on the basis of modulation of the activity of a specific protein (reverse chemical genetics. Section 1.3.1) or its phenotypic effect (forward chemical genetics. Section 1.3.2). Emphasis will be placed on the approaches that may be used to discover useful small molecule tools, and the insights into biological mechanisms that may be accrued. 

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Relationship between Network Connectivity and Discovery of Small-molecule Probes... 

By analogy to the framework for classical genetics developed by Morgan and colleagues, the development of an experimentally driven, computational framework for chemical genetics, which allows the mapping of the functional units (chemicals) that can induce variation in biological systems, holds the potential to revolutionize the discovery of small-molecule probes for basic... 

Discovery of Small Molecule Probes Using a Reverse Chemical Genetic Approach... 

J.S. Potuzak, S.B. Moilanen, D.S. Tan, Discovery and applications of small molecule probes for studying biological processes, Biotechnol. Genet. Eng. Rev. 2004,21,11-77. 

Also, one would be remiss if one did not at least mention the various analytical and diagnostic NMR techniques that have come into prominent use over the last decade, particularly with respect to their applications to drug discovery. Because of the sensitivity of its chemical shift to local environment, 19F NMR has increasingly been used as a probe in the study of structure and dynamics of small molecules, proteins, and other biological systems.32-36... 

The choice of assay type in a drug discovery campaign is complicated. Are you seeking an agonist, an antagonist, or a selective modulator What tools (cell lines, recombinant proteins, small molecule probes, etc.) are at your disposal How many compounds do you want to profile What are your cost and time constraints Each of these issues can modify your determination of the optimal assay for your particular project. 

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