Rational drug design 27/8/02. By Richard Twyman Using structural information about drug targets or their natural ligands as a basis for the design of effective drugs.

Drugs work by interacting with target molecules (receptors) in our bodies and altering their activities in a way that is beneficial to our health. In some cases, the effect of a drug is to stimulate the activity of its target (an agonist) while in other cases the drug blocks the activity of its target (an antagonist).

Finding effective drugs is difficult. Many are discovered by chance observations, the scientific analysis of folk medicines or by noting side effects of other drugs. A more systematic method is large-scale screening experiments where potential drug targets are tested with thousands of different compounds to see if interactions take place (see Combinatorial library screening ).

Rational drug design is a more focussed approach, which uses information about the structure of a drug receptor or one of its natural ligands to identify or create candidate drugs. The three-dimensional structure of a protein can be determined using methods such as X-ray crystallography or nuclear magnetic resonance spectroscopy.

Armed with this information, researchers in the pharmaceutical industry can use powerful computer programmes to search through databases containing the structures of many different chemical compounds. The computer can select those compounds that are most likely to interact with the receptor, and these can be tested in the laboratory.

If an interacting compound cannot be found in this manner, other programmes can be used that attempt, from first principles, to build molecules that are likely to interact with the receptor. Further programmes can search databases to identify compounds with similar properties to known ligands. The idea is to narrow down the search as much as possible to avoid the expense of large-scale screening.

The first drug produced by rational design was Relenza, which is used to treat influenza. Relenza was developed by choosing molecules that were most likely to interact with neuraminidase, a virus-produced enzyme that is required to release newly formed viruses from infected cells.

Many of the recent drugs developed to treat HIV infections (e.g. Ritonivir, Indinavir) were designed to interact with the viral protease, the enzyme that splits up the viral proteins and allows them to assemble properly.

Another well-known drug that was produced by ligand-based design is Viagra. This drug was designed to resemble cGMP, a ligand that binds an enzyme called phosphodiesterase. By blocking phosphodiesterase activity, it was hoped that the drug would help to relax the vascular smooth muscle in the heart and therefore relieve the symptoms of angina. In clinical trials, the effect of the drug on angina was not encouraging, but some of the male patients developed erections. The rest is history!