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Evolving Drug Design

Humans are the product of evolution. Many of the diseases we have to put up with are also either the product, or by-product of evolution. Can we turn this on its head and use evolutionary principles to help us design new medicines?

The Costs Of Medicine

How would you feel if you could cut your shopping bill down to only 0.5% the price it had cost in 1996, if something you required for your everyday life dropped from $15,000 a year down to only $87? What if this product was anti-retroviral drugs which were keeping an HIV infection under control? This massive drop in price has in fact happened with the mass production of generic drugs. These are drugs produced after a patent on a drug has lapsed and as such they are produced and sold cheaply with increased competition since many different companies can produce the same drug. Generic drugs can also be this cheap since they don’t need to recoup massive research and development costs which are incurred by drug companies while moving from identifying a target through to producing a drug for the market. In 2002 it was estimated that this R&D cost was close to $1 billion dollars and the process could take up to 12 years. As such the massive mark-up on prices of these drugs can be justified by the need to turn a profit, as otherwise who would bother with research and development? This gets tricky, however, when considering people less able to afford $15,000 a year just to buy drugs. These prohibitively high costs make new branded drugs totally unfeasible for developing nations and as such a large number of people end up dying due to the need to turn a profit in the developed world.

This does appear to be an impossible problem. If drug prices are forced down then drug companies lose the incentive to research and develop new drugs and so, in the long term, everyone loses out; but keeping the prices high appears as a huge injustice to those less fortunate. A small step towards solving this problem would be to reduce the cost of research and development. One aspect that could be improved is the identification and optimisation of molecules which will bind a specific target as this is how most drugs function. Traditionally this has been done using a process called irrational drug design where a huge library of compounds is tested against a target to see if any of them produce the desired effect. This method isn’t especially efficient but it has nevertheless been responsible for the identification of most modern drugs

Enter Evolution

Several years ago a new method of screening for drug candidates was identified which took advantage of principles which are based around evolutionary biology. This method, called dynamic combinatorial chemistry (DCC) uses a library of molecules which can combine, separate and recombine in new ways. In this way the library contains what is effectively a huge amount of molecular Lego which can be put together to form a huge variety of different things just as the same Lego bricks can make a house, a tree or even a dragon. If a target, such as an enzyme which you want to block, is added to the mixture then any of these randomly combined molecules which bind to the enzyme are stabilised. As such, these molecules become enriched within the population at the expense of other molecules.

In this way drug design is approximating to an evolutionary process although there isn’t the reproduction of successful molecules, instead there is the selective accumulation of these ‘fitter’ molecules. This method is far from perfect however since in order for the process to work covalent bonds need to be formed, broken and reformed. That isn’t too much of a problem when using DCC to bind inorganic molecules, but the conditions for using it with biological molecules are much more stringent since the biological target is much more eaily damaged, which damage would prevent it being used as a template. As such, only a reduced number of reactions can currently be catalysed and this leads to a restricted number of molecules being formed. This will hopefully be remedied in the future and could lead to a much more rapid process of not only drug discovery but also more efficient optimisation. This could occur qiuckly since once a lead has been found a more restricted library can be created allowing for finer optimisation to take place using the original molecule as an initial template.

This stage of research is clearly not the only part of the drug discovery process. It is also not the most expensive part, compared with animal tests and subsequent clinical trials. However, if every step can be improved just a bit maybe we can hope to see a solution to the problem with drug discovery and the developing world.

Written by Ed Roberts