Rational Drug Design

Many medicines have been developed by traditional drug discovery methods, in which a myriad of naturally occuring compounds have been surveyed for their ability to control disease. However, the explosion in the fundamental knowledge of biological protein interactions has enabled a rational approach to drug design based on theory and structural biology. The impact pf structural biology on the design of medically important drugs is exemplified by the development of the anti-influenza drug Relenza. This work was carried out within CSIRO and was the first structure-based anti-viral drug that was developed, and also a very early example of the rationally-based drug design methodologies. Subsequently, the new generation of drugs active against HIV such as HIV-protease inhibitors were developed by a similar methodology. Other examples have been the development of the anti-inflammatory inhibitors that are selective inhibitors of the COX-2 enzyme. There are many drugs undergoing late-stage clinical trials at present for a number of human diseases ranging from cardiovascular disease to cancers that are based on information discovered by structural biology. It is expected that this approach to finding solutions to human health problems will accelerate in the future, as it is becoming increasingly important in the fight against newly-emerging and re-emerging viral and microbial diseases.

rational drug design is currently being applied to many areas of drug development. Anti-viral developments include efforts to abate the HIV pandemic; the serious human health risk posed by the hepatitis C virus, which is mutating a rate that makes vaccine treatment ineffective; and measles. which continues to kill over a million children in Africa alone. Currently, no drugs are available for many third world protozoan pathogens like sleeping sickness, and malaria is becoming increasingly resistant to current drug therapy, as are several microbial diseases like tuberculosis and staphylococcus aurelius infections.

Almost all drugs used in the treatment of cancer cause serious side effects because they lack selectivity for tumours over normal tissues. Selective activation relies on successful exploitation of the differences between the environment in tumours and that in healthy tissues. Tumour hypoxia, the lower than normal oxygen levels present in solid tumours, is the result of the rapid growth and possr vascularization of tumours. For a drug to be activated in an hypoxic environment, it must have an inactivated higher oxidation state and an activated lower oxidation state. To date, the development of hypoxia-selective agents has been carried out in the absence of information about the oxidation status of the agents in tumours and, in particular, how this status is affected by the degree of hypoxia. Extensive investigations of Co and Pt anti-cancer drugs using x-ray absorption spectroscopy are in progress to determine the oxidation state in situ in different regions of tumours, and in models of hypoxic tumours. Simultaneously, the project will provide information on the relationship between reduction potential and the extent of activation in hypoxic environments.

Vibrational spectroscopy and circular dichroism are complementary techniques that are able to monitor the take-up of anti-cancer drugs in cells and their effect on the conformational changes that these cause in critical proteins. Synchrotron light will add a new dimension to these studies because it will be possible to follow these processes in real time.

Cobalt-, copper-, nickel-, and zinc-based anti-inflammatory compounds are potent vetinary drugs and are likely to enter human clinical trials in the near future. X-ray absorption spectroscopy has been used extensively in the characterization of new drugs in the solid state, solution, pharmaceutical formulations and biological fluids. This research has been essential in determining the stability of the drugs in pharmaceutical preparations. X-ray absorption spectroscopy on the micron scale, which will be possible using the microfocus spectroscopy beamline at the Australian Synchrotron, is able to image the uptake and metabolism of metal-containing pharmaceutics in cells and tissues. This will provide a better understanding of the pharmacology of these drugs for the development of better and safer systems.