Reverse Pharmacology and Drug Discovery: Artemisia annua and Its Anti-HIV Activity

van der Kooy, Frank

There are various ways in which new drugs can be developed. One approach is in silico drug design based on our existing knowledge of the biology of a specific disease and the specific target site binding chemistry. Based on this knowledge, a range of molecules will be designed and synthesised after which they will be tested in in vitro bioassays for activity and toxicity. The best candidates, called lead compounds, will then be “fine-tuned” by chemical derivatisation in order to improve their activity and/or to reduce their toxicity. Lead compounds are then tested in various animal models before entering clinical trials in people. Another approach is to screen a large number of biological samples (plants, bacteria and fungi) for activity against a specific disease. Any active extract, consisting of many compounds, will be fractionated by chromatographic techniques, and each fraction will be tested for in vitro activity. Active fractions will again be fractionated until the active compound is identified. This process, also called bioguided fractionation, can go through a number of fractionation cycles before the active compound is identified. The active compound will be chemically derivatised in order to improve its properties before in vivo animal studies will be conducted. Based on these test results, the most promising lead compounds will then be tested in clinical trials in people. There are however a number of shortcomings with both approaches. It is expensive, time consuming, makes use of in vitro bioassays and it suffers from a very low success rate. Due to these shortcomings, it is currently estimated that the development of one new drug costs around $1–1.5 billion, simply because so many lead compounds fail during clinical trials. Keeping these high costs in mind, one would think that all registered drugs are effective and importantly non-toxic. Unfortunately, this is not the case, as there are a number of drugs currently on the market that are causing severe side effects and whose efficacy should be questioned. This holds true particularly for cancer chemotherapeutics. It was estimated that cancer chemotherapy improves the average 5-year survival rate of patients (for all cancer types) by only 2 % (Morgan et al. 2004). Another relatively unknown fact is that each year, 200,000 people die in the EU due to adverse drug reactions (all types of drugs), highlighting the severe shortcomings of the drug development and drug licensing pipelines (Archibald and Coleman 2012). To put this into perspective, there are a large number of drugs that work perfectly well and are safe to use, but we have to concede that our approach to drug discovery and our overall approach to health care suffers from some major problems.