New Pathways to Discovery

Building blocks, biological pathways, and networks Complex elements—from individual genes to entire organs— work together in a feat of biological teamwork to promote normal development and sustain health. These systems 

Computer-assisted drug design (CADD), also called computer-assisted molecular design (CAMD), represents more recent applications of computers as tools in the drug design process, though it does not replace the human element in analyzing the data. 

In considering this topic, it is important to emphasize that computers cannot substitute for a clear understanding of the system being studied. That is, a computer is only an additional tool to gain better insight into the chemistry and biology of the problem at hand. 

New perspectives on the complexity of G-protein-coupled receptor (GPCR) signaling and the increased resolution of existing tools for studying GPCR behavior has led to the conception of new hypotheses that affect the discovery of drugs 

Several disciplines of research have emerged to create remarkable new opportunities for drug development. Some important ones are described in the following sections. 

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Hydrogen cyanide has been discussed as a precursor to amino acids and nucleic acids. It is believed by some, for example, that HCN played a part in the origin of life. Although the relationship of these chemical reactions to the origin of life theory remains speculative, studies in this area have led to discoveries of new pathways to organic compounds derived from condensation of HCN. 

Particularly important to the pathways of modular synthases is the incorporation of novel precursors, including nonproteinogenic amino acids in NRP systems [17] and unique CoA thioesters in PK and fatty acid synthases [18]. These building blocks expand the primary metabolism and offer practically unlimited variability applied to natural products. Noteworthy within this context is the contiguous placement of biosynthetic genes for novel precursors within the biosynthetic gene cluster in prokaryotes. Such placement has allowed relatively facile elucidation of biosynthetic pathways and rapid discovery of novel enzyme mechanisms to create such unique building blocks. These new pathways offer a continued expansion of the enzymatic toolbox available for chemical catalysis. 

This chapter focuses on a novel antibiotic discovery paradigm. Metallo-hydrolases and Mur ligases are used to illustrate this approach. New methods to identify and prioritize targets, develop screens, and evaluate new inhibitors are discussed. New developments in enzyme-based assays, such as pathway assays, are also presented. This new approach is opening new venues for screening targets that are difficult to screen because substrates are not easily available. 

We measured the electrical conductivity of Pt-C nanocomposites using two-point measurements. In a representative example the NP-polymer hybrid had a conductivity of 2.5 mS cm-1, which increased to 400 S cm-1 upon pyrolysis. Despite the presence of carbon, to the best of our knowledge this value represented the highest electrical conductivity yet measured for ordered mesoporous materials derived from block copolymers. This discovery creates a potential pathway to a new class of ordered mesoporous metals made from nanoparticles of different elements and/or distinct compositions. Such nano-heterogeneous mesoporous metals may have a range of exceptional electrical, optical, and catalytic properties. 

One of the more exciting and recent advances in the field of plant biochemistry has been the discovery of the mevalonate-independent pathway for the biosynthesis of isoprenoids (Fig. 10.4). This new pathway, referred to a the methyl-erythritol-phosphate or MEP pathway for the first intermediate committed solely to the biosynthesis of isoprenoids, was first discovered in prokaryotes capable of accumulating hopenes, the equivalent of eukaryotic sterols. 6,17 The MEP pathway has since been confirmed in plants and, not surprisingly, has been localized to chloroplasts.18 Operation of the MEP pathway is intimately related to the reactions of CO2 fixation and photosynthesis, as evidenced by the two immediate precursors pyruvate and phosphoglyceraldehyde for this pathway. Two important features of this pathway are that mevalonate is not an intermediate in the plastidic synthesis of isopentenyl (IPP) and dimethylallyl diphosphate, (DMAPP), and this pathway... 

The need exists to expand the repertoire of tools available for weed management systems. What little we know of the molecular target sites of natural phytotoxins indicates that they are inhibitors of a broad array of enzymes and other molecular targets that have not been the focus of herbicide discovery efforts [1]. At present, commercially available herbicides target a relatively limited number of enzymes and metabolic pathways. The discovery of new target sites is a growing emphasis of pesticide companies, especially since the U.S. Food Quality Protection Act has combined food tolerance levels of pesticides with the same molecular target sites. 

Nitroxide-Mediated Controlled Radical Polymerization (NMCRP) was first discovered by Solomon et al., who patented their discovery in 1985 [205]. This opened up new pathways in the field of free-radical polymerization. Polymer architectures, which were the domain of the anionic polymer chemist, became accessible to the free-radical polymer chemist. However, it was not until the work of Georges et al. [206] was published in 1993, that the world of polymer chemistry became aware of the possibihties of this new class of free-radical polymerization. This was the beginning of what is today one of the leading topics in free-radical polymer chemistry Controlled or Living Free Radical Polymerization. This initiated the search for new Controlled or Living Free Radical Polymerization techniques, and soon afterwards other methods (which will be discussed later) were developed. 

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