Figure 1 |  The nature of chiral molecules. Chirality is the spatial arrangement of points or atoms that are non-superimposable on its mirror image. In the case of organic compounds found in living organisms, this means compounds that contain a carbon atom that is bonded to four different chemical groups, such as in the mirror image structures, or enantiomers, of limonene shown here. R and S denote the configuration of the atoms in the structure. These enantiomers can form naturally and have differing biological activities; in this case, the R-form smells of oranges and the S-form smells of lemons. This is because our nasal receptors are also made up of chiral molecules that recognise the difference.

Chiral molecules were first discovered in 1848, when Louis Pasteur discovered that a crystalline deposit formed on wine casks during fermentation (which he called 'racemic acid') contain equal amounts of left- and right-handed crystals of sodium ammonium tartrate. Pasteur showed that these have different properties by meticulously separating the two forms using a pair of tweezers - when he shone polarized light through them, one form bent the light clockwise, the other bent it anticlockwise. Unlike the racemic situation that Pasteur stumbled on, the chemistry of life selects for specific versions of chiral compounds, choosing to use only left-handed forms of amino acids and right-handed forms of sugars, a phenomenon called homochirality. The ability of biological molecules to discriminate between these enantiomers is vital for living systems. In 1953, the theorist F. C. Frank proposed how this selection process occurs - a tiny amount of one particular chiral form can become amplified into an excess over the other, through a process known as autocatalysis. Chiral molecules are already exploited by pharmaceutical companies, but more so to isolate the therapeutically more active form of a drug from the existing racemic drug mixture. But, as biology uses chirality to create function, said Trost, why not use enantioselectivity for drug discovery and not just the development process. We've explored very little 'reaction space', and new reactions are important. This can be done, said Trost: the world's biggest selling drug, Pfizer's statin Lipitor, was created from a desire to motivate chemists to exploit a new reaction. Chirality, however, is haunted by ghosts from the past, as this is synonymous with the thalidomide tragedy. It is generally thought that this tragedy arose because the drug was a mixture of both enantiomers. One enantiomer had the desired sedative therapeutic properties, but its mirror image induced the gross foetal abnormalities that led to the withdrawal of the drug. But Israel Agranat, from The Hebrew University of Jerusalem, said this has turned out to be a myth: in the body, individual enantiomers of thalidomide are both converted rapidly to the racemate mixture. Any difference in toxicity between the enantiomers would be blunted by this rapid conversion to both forms. The message here is that a wealth of data needs to be considered in full when considering chirality in discovering drugs. Christopher Lipinski, formerly of Pfizer, said that companies try not to have a chiral centre in a drug molecule as this is likely to result in more metabolites being produced, which could make analysis of these products more difficult or time-consuming. As medicinal chemists like to keep structures simple, if they find a chiral centre in a compound the first thing they will do is to try to get rid of it. But Trost said that such complexity might be a good strategy as it could provide a competitive advantage against companies that create generic versions of drugs. Pharma is good at creating complex compounds, generic companies less so, so more complexity could make generic compounds harder to make. In support of this, Victor Hruby, from the University of Arizona, described another chiral molecule, the sweetening agent aspartame. One enantiomer has a bitter taste, with the odour of caraway, while the mirror image molecule has a sweet taste. Aspartame has been off patent for years, said Hruby, but is still produced by one company, mainly because it is too expensive for other companies to build the plant that makes and isolates the desired version, and therefore no-one is willing to bear this expense. But despite the problems with introducing chirality into de novo design of small-molecule compounds, it's still worth pursuing, said Trost. We throw away a lot of compounds because they can't make them in a time-dependant manner, he said. This is hopefully something that methodologies such as improvements in synthesizing chiral compounds will resolve.