Editorial [Hot Topic: Chemical Effectors in Drug Discovery (Guest Editor: William F. Michne)]

Chemical Effectors in Drug Discovery Over the past ten to fifteen years the pharmaceutical industry has become increasingly dependent on high throughput screening against single molecular targets as a source of leads to support drug discovery. Several technologies have facilitated this dependence. The sequencing of the human genome, as well as those of several human pathogens, along with advances in bioinformatics, continues to provide new molecular targets whose functions can presumably be influenced, by small molecules, so-called “chemical effectors,” in ways that ultimately result in beneficial effects for the patient. Advances in combinatorial chemistry have provided large libraries of compounds that can be screened for their interactions with the target molecules. There have also been advances in the development of whole cell assays for high throughput screening to influence phenotype. Academic laboratories, as well as some industrial groups, are turning to such assays for the identification of additional new targets, and molecules that can be used as probes of target function. There have been several discoveries that testify to the validity of these approaches, although the rate of discovery of new compounds as drug leads and function probes has not reflected the early optimism. The key to success in any screening campaign is the nature, quality, and size of the screening library. Much has been written about the most effective way in which to design a screening library. At the most elementary level, one might consider synthesizing all drug-like molecules. The total number of such molecules has been estimated to be on the order of 1062, a “virtual library” that contains all of the best drugs we can ever find. Often discussed cavalierly, the sheer enormity of the number is incomprehensible. How can we ever hope to discover the best compounds in this set, and how will we know when we have done so? The answer is that we can't and we won''t. We must continue to try, however, as the needs of human medicine remain daunting, and will for some to come. Our emerging experience seems to be indicating that large, diverse libraries are not very productive at generating leads. This continues to be true after filtering the libraries for "drug-like" properties. As a result there is an increasing appreciation that biological activity is not uniformly distributed throughout chemistry space, but rather exists in small and widely dispersed regions. It is thus easy to understand why libraries based solely on considerations of structural diversity have not been particularly productive. Our plight is further confounded by the fact that many molecules of similar structure have quite different biological activities, whereas many of quite different structure have similar activities. While some of this can be explained by knowing the structure of the target and the nature of the interaction, the fact is that we understand very little about why a given molecule does or does not exhibit biological activity. Many groups in industry and academia are studying this problem from different points of view. It was the intent of this editor to bring together in one issue of Current Topics in Medicinal Chemistry a number of reviews of this topic written by authors who would concentrate on work carried out at their own institutions. The reader would then have access in one place to the current results of the leading groups working in the area. The effort was modestly successful in that we were able to commission five reviews with a balance between industry and academia. It is somewhat disappointing that others in the field who have published significant results chose not to participate, although one can understand their reluctance for strategic business reasons. Nevertheless, I am delighted with the reviews that were received, and hope that you, the reader, will find them both informative and enjoyable.