“...we hope to raise awareness in drug discovery of the difference between designing tools and candidate medicines.”

There is a growing interest in post-genomic biology as to the advantage of returning to the application of chemical tools to dissect functional biology, particularly in exploring the temporal and the dynamic of protein functions. The field of chemical biology holds great promise not only for increasing our knowledge of biological systems, but also as a potentially rich source of novel candidate medicines and drug targets. We attempt to open up a discussion as to what precisely are the limitations of chemical biology. We also consider the differing chemical properties and selection criteria of a compound, whether one’s goal is drug discovery or biological knowledge discovery. We hope our paper provides a balanced argument on the pros and cons of the application of chemical tools to biology and drug discovery. We wished to share a hard lesson learned from industry, that the discovery of a chemical tool for a target, although incredibly useful, does not necessarily mean it is a lead compound in the development of a new drug.

The philosophical basis of this paper is a synthesis of our previously published work on the chemical and biological properties of drug space. We plan to publish new methodologies and insights in 2006, which further support the arguments in the paper. We hope the ideas in the paper are useful considerations in the design of chemical libraries for chemical biology studies, whether the goal is tool discovery or drug discovery. Likewise, we hope to raise awareness in drug discovery of the difference between designing tools and candidate medicines.

While not all compounds with biological activity are suitable as drugs, they can still be extremely valuable as tools in the dissection and investigation of biological mechanisms. Understanding the landscape of chemical space where specific areas are made richer by biological targets of different types, and where only certain of these areas are made richer for drugs, we hope we can increase the potential gains to science and society from the field of chemical biology.

We've been interested in the paradox that, as we have invested more in biomedical research and increased our knowledge, we have conversely seen a steady decline in the number of new drugs coming to market. Building upon the "Rule-of-Five" (ROF) and "druggable genome" ideas, we've been interested in how we can understand the factors that make drug discovery successful and how we can apply these approaches to identify those compounds in chemical space and the targets in biological space which are more likely to yield new medicines.

There is a growing enthusiasm for chemical biology amongst both public and philanthropic funding bodies in recent years. For example, the United States National Institutes for Health (NIH) "Roadmap" includes a significant investment in molecular libraries and high-throughput screening initiative. The pharmaceutical industry has been investing in large-scale chemical libraries and screening for over fifteen years and has learned many hard, salient lessons. Part of the excitement in these initiatives is the impetus to open up and encourage non-traditional routes to drug discovery. We wish to see these new public initiatives succeed; hence we want to make sure they start off on the right track by understanding the distinctions, in terms of chemical properties, between the discovery of chemical tools and prototype drugs, in order to ensure success for these new ventures.