Current Topics in Medicinal Chemistry - Volume 5, Issue 4, 2005

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.

Target-Related Affinity Profiling (TRAP*) is a computational drug discovery technology that is based on ‘affinity fingerprints’, which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular descriptors derived from chemical structures and shown to be a useful alternative for lead discovery. The TRAP screening process is described and two example applications are presented: I. the discovery of novel inhibitors of human intestinal carboxylesterase, and II. the discovery of novel inhibitors of cyclooxygenase-1 through the use of the affinity fingerprints of known cyclooxygenase-1 inhibitors. A summary of the complementary advantages of TRAP screening technology compared to traditional approaches to drug lead discovery concludes the review.

Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer. These approaches could involve cell replacement therapy and / or drug treatment to stimulate the body's own regenerative capabilities by promoting survival, migration / homing, proliferation, and differentiation of endogenous stem / progenitor cells. However, such approaches will require identification of renewable cell sources of engraftable functional cells, an improved ability to manipulate their proliferation and differentiation, as well as a better understanding of the signaling pathways that control their fate. Cell-based phenotypic and pathway-specific screens of synthetic small molecules and natural products have historically provided useful chemical ligands to modulate and / or study complex cellular processes, and recently provided a number of small molecules that can be used to selectively regulate stem cell fate and developmental signaling pathways. Such molecules will likely provide new insights into stem cell biology, and may ultimately contribute to effective medicines for tissue repair and regeneration.

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.

In some instances, small molecules can restore function to proteins that are impaired by genetic mutations. There are now many examples where non-specific molecules or specific ligands can act as chemical chaperones to fold proteins or stabilize folded proteins harboring genetic mutations. In contrast a few recent examples have shown that functionally impaired proteins that are stably folded can be “functionally rescued” by appropriate small molecules. Compounds that can rescue functionally impaired proteins may provide new strategies for the treatment of genetic diseases such as rickets and resistance to thyroid hormone (RTH). In addition mutant-complementing analogs and substrates that act exclusively on mutant proteins are providing important tools for the study of complex biological systems that are controlled by molecules that have multiple cellular targets.

This review aims to give an overview of current good practice in the prosecution of Lead Generation. It will assess experiences across the field as judged from the contents of the limited number of peer-review disclosures to date. It will also rely heavily on the experiences of the authors from many campaigns within this organisation. Its focus will be on the assembly of an appropriate compound collection for application in High Throughput Screening (HTS), the prosecution of HTS, the profiling of HTS output and, lastly the Hit-to-Lead optimisation of selected HTS output. Excluded from the scope are detailed aspects of library design [1], parallel synthesis [2], virtual library applications [3], virtual screening [4] and fragment screening [5] approaches, all of which have been the subject of recent reviews.