Forward chemical genetics mechanisms

Like its genetic counterpart, forward chemical genetics relies on a phenotype of interest to guide the selection of biologically active small molecules that modulate a particular biological system or mechanism (Fig. 6-3) [5-7]. Overall, this approach entails a three-step process that... 

To summarize, as shown in Table 6-2, in a forward chemical-genetic screen, scientists start with a phenotype to find the protein or proteins responsible for it, and in a reverse chemical-genetic screen, the starting point is a protein of interest. Completing the trio of arrows in the discovery cycles in both cases provides valuable tools for the dissection of biological systems and mechanisms. 

Fig. 6-24 Future challenges for forward chemical-genetic discovery of probes of biological mechanisms.

Forward chemical genetics approaches start with compounds that cause a particular phenotype in a biological system (e.g., ADEPs inhibit cell growth and trigger filamentation). Subsequently, the target of this small molecule and its mechanism of action are elucidated. Hence, the forward chemical genetics workflow is from compounds to gene. Usually, in vivo experiments are carried out ahead of in vitro experiments. 

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. 

In addition to the fundamental importance of electronic conductivity of molecules as intriguing as DNA and proteins, electronic conductivity of DNA-based molecules holds other perspectives. Charge transfer along the DNA double-strand has been forwarded as an in vivo mechanism for radiation and chemical damage of the DNA-based genetic system, and for... 

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