Current Drug Discovery Technologies - Volume 5, Issue 3, 2008

The availability of large collections of small-molecule inhibitors of protein interactions would bear a tremendous impact both on academic and therapeutic research. The past recent years have seen a marked acceleration in the discovery of protein interaction inhibitors, through structure-based drug design but mostly through screening efforts. This article attempts to review the impressive number and variety of in vitro and cellular screening assays that have been developed and, for most of them, used successfully to identify smallmolecule inhibitors of protein interactions. Various strategies aimed at improving hit rates are also reviewed, and future challenges to improve discovery success rates are discussed. The growing list of protein interaction inhibitors and the large arsenal of screening methods, now available to most laboratories or screening facilities, will probably convince an increasing number of academic and industrial scientists that protein interactions are more druggable than once feared, and that their respective research interests would greatly benefit from the discovery of protein interaction inhibitors.

The pivotal role of proteases in many diseases has generated considerable interest in their basic biology, and in the potential to target them for chemotherapy. Although fundamental to the initiation and progression of diseases such as cancer, diabetes, arthritis and malaria, in many cases their precise role remains unknown. Activity-based chemical proteomics-an emerging field involving a combination of organic synthesis, biochemistry, cell biology, biophysics and bioinformatics-allows the detection, visualisation and activity quantification of whole families or selected sub-sets of proteases based upon their substrate specificity. This approach can be applied for drug target/lead identification and validation, the fundamentals of drug discovery. The activity-based probes discussed in this review contain three key features; a ‘warhead’ (binds irreversibly but selectively to the active site), a ‘tag’ (allowing enzyme ‘handling’, with a combination of fluorescent, affinity and/or radio labels), and a linker region between warhead and tag. From the design and synthesis of the linker arise some of the latest developments discussed here; not only can the physical properties (e.g., solubility, localisation) of the probe be tuned, but the inclusion of a cleavable moiety allows selective removal of tagged enzyme from affinity beads etc. The design and synthesis of recently reported probes is discussed, including modular assembly of highly versatile probes via solid phase synthesis. Recent applications of activity-based protein profiling to specific proteases (serine, threonine, cysteine and metalloproteases) are reviewed as are demonstrations of their use in the study of disease function in cancer and malaria.

Annonaceous acetogenins are a large family of natural polyketides. So far, more than 430 compounds have been isolated. Biologically, they are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Herein, we would like to conduct an overview on the progress of the total synthesis, structural revisions, structure activity relationship for the inhibition of complex I, and action mechanism.

Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.

Neurotransmission is essential to physiological processes of cellular communication. The search for new molecules that may influence neurotransmission systems is an open field with possible impact on several pathophysiological conditions or diseases: Alzheimer's disease, Parkinsonism and myasthenia gravis, etc. The present review describes the most important aspects of cholinergic neurotransmission, as well as natural and synthetic compounds that, as clinical or experimental drugs, are able to influence this transmission. The pharmacological effects of substances that bind to muscarinic or nicotinic cholinergic receptors, along with their corresponding affinities will also be presented.

Despite increasing investment in drug discovery and development, only around one in every ten new medicinal products that progresses to clinical testing ever reach from the registration stage. Approximately half of all drug failures are attributed to problems with efficacy and toxicity not anticipated from preclinical studies. As a consequence, the pharmaceutical industry is adopting a much more flexible and multi-disciplinary approach to drug discovery and development. Indeed, the line between basic and applied science is constantly being eroded, not least because of the increasing sophistication of therapeutic procedures and the complexity of the diseases that they aim to treat. Here, we look at the new technologies that are being explored as a way of reducing drug attrition rates and the development of chemical drugs and biotherapeutics. Specifically, we will consider the ways in which genomics and related disciplines, engineered cell-based and microfluidics systems, and nanotechnologies are being developed and used alongside in silico platforms during early drug pharmacokinetics and toxicity studies. The way in which information from such systems biology-oriented approaches can be integrated with information from animal based preclinical safety, toxicological and pharmacological studies on investigative medicinal products is considered, in view of its current and possible impact on clinical trial design.

Cancer is one of the major leading causes of death all over the world. Primary and secondary bone tumors can significantly deteriorate the quality of life (QOL) and the activity of daily living (ADL) of the patients. These unwelcome diseases become a social and economic burden seriously. Thus, more effective therapies for both primary and secondary bone tumors are actually required. Bone homeostasis depends on the strictly balanced activities between bone formation by osteoblasts and bone resorption by osteoclasts. Imbalance of bone formation and resorption results in various bone diseases. Both primary and secondary bone tumors develop in the unique environment bone, it is therefore necessary to understand bone cell biology in tumoral bone environment. Recent findings strongly revealed the significant involvement of the receptor activator of nuclear factor κB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad, the key regulators of bone remodeling in bone oncology. Indeed, RANKL/RANK blocking successfully prevented the development of bone metastases. Furthermore, some cancer cells express RANK which is involved in tumor cell migration. Thus, the regulation of this triad will be a rational, encouraged therapeutic hot spot in bone oncology. In this review, we summarize the accumulating knowledge of the RANKL/RANK/OPG triad and discuss about its therapeutic capability in primary and secondary bone tumors.