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Dobson (2004): Chemical space and biology
In the abstract, the author states that chemical space "encompasses all possible small organic molecules, including those present in biological systems" and the exploration of this space has "greatly enhanced our understanding of biology" and has "led to the development of many of today's drugs". "The discovery of new bioactive molecules, facilitated by a deeper understanding of the nature of the regions of chemical space that are relevant to biology, will advance our knowledge of biological processes and lead to new strategies to treat disease."
The simplest living organisms can function with just a few hundred different types of such molecule, and fewer than 100 account for nearly the entire molecular pool. Moreover, it seems that the total number of different small molecules within our own bodies could be just a few thousand. So, it is clear that, at least in terms of numbers of compounds, 'biologically relevant chemical space' is only a minute fraction of complete 'chemical space'[.]
What is important is that biological molecules "are packed together to an extraordinary degree within cells":
A space-filling representation of a typical cell illustrates how molecular species are crowded together in its complex organizational structure. Such 'molecular crowding' is likely to be important in many facets of biological chemistry. For example, binding affinities and the rates of self-assembly can change by orders of magnitude as a result of this phenomenon. Crowding is therefore an important factor to consider when using data derived from in vitro studies in dilute solution to understand processes taking place in vivo.
The author mentions that "[t]echniques such as X-ray crystallography, nuclear magnetic resonance (NMR) and mass spectrometry have already revolutionized our understanding of the structure and function of biological molecules" and there are new techniques to come, such as "cryoelectron tomography".
Regarding drug discovery:
[W]ith the immense developments in combinatorial methods over the past decade or so, huge arrays of new molecules can be produced in relatively short periods of time. Together with rapid screening methods, the drug-discovery process has been moving into uncharted territory; seemingly endless numbers of potentially active compounds are becoming available. As our knowledge of even the most complex aspects of biology at a molecular level expands, we can increasingly use rational arguments in the design of potential therapies and of new molecules that are promising to test or screen. [...] [T]he examination of molecules in silico for their ability to bind to specific targets already plays an important part in screening strategies, although such 'virtual screening' approaches have yet to achieve their full potential in the drug-discovery process.
Also, natural compounds from bacteria or other microorganisms might serve as the basis of new drugs:
Remarkably, however, it has been estimated that only 0.1% of all bacterial strains - the richest source of new biological molecules - has been cultured and analysed. Thus, as Clardy and Walsh discuss in this issue, there is a vast harvest of new natural products, perhaps running to millions of new compounds, waiting to be gathered from previously unexplored strains of living organisms (mainly bacteria, plants and fungi). Moreover, there are now opportunities to manipulate nature's 'production lines', for example, by using mutagenesis and gene shuffling to induce microorganisms to create new biologically active molecules, and hence to generate large libraries of new 'natural products'.
There is also a paragraph about "chemical genetics":
Using small molecules to probe biological systems is now often described as 'chemical genetics' or 'chemical genomics'. As well as the issues of diversity and specificity, cells may have evolved mechanisms to protect some of their most vital proteins from interference by small, extraneous molecules. Another major issue in chemical genetics concerns the quality of the data that are generated using various assay technologies; screening the same biological target with three different types of assay was recently found to give a set of hits that is consistent from assay to assay in only about 30% of cases.
DNA and RNA are becoming increasingly interesting, as well as oligosaccharides:
[V]arious RNA technologies are currently generating a great deal of interest. That RNA molecules play an important part in biological chemistry is well established, notably as the catalytic ribozymes that are involved in many important biological reactions, not least protein synthesis. Moreover, RNA interference (RNAi), in which synthetic RNA fragments are designed to interfere with the normal expression of specific genes, is becoming an important tool for exploring gene function[.] [...] Furthermore, members of a previously neglected class of molecules, the oligosaccharides, are emerging as biological tools, now that efficient methods for sequencing and synthesizing these complex molecules are being developed.
The authors conclude:
A rich array of data on the effects of small molecules on biological systems is accumulating, mainly from large-scale screening exercises[.] Analysis of such databases, using the types of computational method pioneered by the flourishing bioinformatics community, should lead to major advances, both in our understanding of biological chemistry and in our ability to identify promising therapeutic compounds and therapeutic targets. [...] With increasingly diverse, reliable and accessible databases of information about the effects of new chemical compounds on specific biochemical processes, we shall be able to understand much more about the nature of biologically relevant chemical space. In addition, we shall learn more about the types of compound that might make good drugs by analysing the behaviour of a much wider range of small molecules than the miserly number used by our bodies for so many purposes from generating energy to building arsenals of macromolecules. In this regard, among the most exciting recent developments are efforts to generate public databases of chemical information, and the establishment by the US Government of Molecular Libraries Screening Centers. The latter initiative is designed to give public-sector researchers access to an initial library of around 500,000 small molecules for use in probing a diverse range of biological systems. These compounds may lead to new research tools and could aid the development of new drugs or the discovery of new applications for existing ones (see NIH Molecular Libraries Initiative).
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