Chemical space — which encompasses all possible small organic molecules, including those present in biological systems — is vast. So vast, in fact, that so far only a tiny fraction of it has been explored. Nevertheless, these explorations have greatly enhanced our understanding of biology, and have 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.
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At a glance
: Schematic representation of a crowded cell.
An array of different molecules can function independently under extremely crowded conditions, partly because of judicious distributions of oppositely charged polar groups on the molecular surfaces
. However, such systems are in some ways extremely fragile. For example, a mutation that alters just one amino acid in the haemoglobin molecule (replacing a charged carboxylic acid with a methyl group) can stimulate massive aggregation and give rise to a fatal genetic disease, sickle-cell anaemia 38 . More generally, many disorders of old age, most famously Alzheimer's disease, result from the increasingly facile conversion of normally soluble proteins into intractable deposits that occur particularly as we get older (see http://www.horizonsymposia.com/ for the Horizon Symposium ‘Protein Folding and Disease’, and ref. 8, 39 40). Many of these aggregation processes involve the reversion of the unique biologically active forms of polypeptide chains into a generic and non-functional ‘chemical’ form . Adapted with permission from D. Goodsell. 41
: Comparison of the properties of different classes of molecule.
A large database that contained compounds from combinatorial chemistry (
a), natural products ( b) and drugs ( c) was analysed on the basis of a variety of molecular properties . To visualize the diversity of these compounds on the basis of these properties, a statistical approach known as principal component analysis was used. Plots of the first two principal components — which explain about 54 19 % of the variance in the properties analysed — are shown. Combinatorial compounds cover a well-defined region in diversity space given by these principal components. Both drugs and natural products cover all this space, as well as a much larger additional region of space. It is of particular interest to note the similarity of the plots of natural products and successful drug molecules. Adapted with permission from ref. 19.