Chemical genetics biological 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. 

For chemical genetics to truly compete with classical genetics, and for it to function as a general approach to dissecting biological mechanisms, there... 

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

The Bayesian network approach is promising but there are limitations we have mentioned already the restriction to acyclic graphs (no loops in the network) and the issue of Markovian independence. There are others the presence of causal connectivity, as discussed in chapters 5 and 6, can be implied, can be indicated, but can not be determined. Finally, there is no rational basis, as yet, for connecting a Bayesian network with a chemical, biological, or genetic reaction mechanism the equivalents of the concepts of temporal dynamics of reaction mechanisms, of rate coefficients, and of reversibility of elementary reactions are missing from Bayesian networks. 

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. 

The Chemical Genetic Approach The Interrogation of Biological Mechanisms with Small Molecule Probes... 

The chapter is not an exhaustive review of chemical genetics the field, and its impact on our understanding of fundamental biological mechanisms, has already been comprehensively reviewed elsewhere. Rather, the chapter will emphasise the approaches that may be used to diseover small molecule probes, the solutions that address the challenges raised by chemical genetics, and the insights into fundamental biological mechanisms that may be revealed. 

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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