Current Drug Discovery Research Articles

High Throughput Electrophysiology: New Perspectives for Ion Channel Drug Discovery

Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels. A cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion channel targets accessible for drug screening. Specifically, genuine HTS parallel processing techniques based on arrays of planar silicon chips are being developed, but also lower throughput sequential techniques may be of value in compound screening, lead optimization, and safety screening. The introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery.

Is combinatorial chemistry on the right track for drug discovery?

Critical to the effective implementation of high throughput methods of synthesis is the necessity for a significant supporting level of automation. There are a number of critical issues associated with the successful introduction, and supporting role, of automation of small molecule chemical synthesis. Clearly there are needs for automation to increase drug candidate synthesis throughput. Automation of repetitive and laborious tasks associated with the synthesis process can release skilled chemists to apply their talents to the more challenging investigational aspects of developing new synthetic protocols. This provides continuity in the compound supply pipeline and ensures an optimal use of the automated platform for compound production. The very high fidelity of performing repetitive processes that can be managed through automation also removes some of the limitations and errors associated with more fallible human operators. This can include very difficult tasks associated with tracking data, and general information and inventory management. Taken collectively, these attributes associated with automation can lead to greater efficiencies, throughputs and improved allocation of human resources with concomitant reductions in costs associated with current day and future drug discovery. In our library development/synthesis paradigm, we feel that automation support must be invoked early in the process and that this automation support must continue throughout the project.

Appetite suppression based on selective inhibition of NPY receptors.

The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y(1) receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y2 and NPY Y5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.

RNA and RNA-protein complexes as targets for therapeutic intervention.

Today, the majority of pharmaceuticals developed to treat cancers and viral/bacterial infections target cellular, bacterial or viral proteins known to be associated with a given pathology. Although proteins are the focus of most current drug discovery efforts, exciting new research has recently begun which aims to exploit ribonucleic acid (RNA) and RNP particles as novel targets for pharmaceutical development. These RNA-targeted research efforts have been fueled by an increased appreciation for the central role played by RNA and RNA-protein interactions in many biological processes and diseases, together with a better understanding of RNA structure and an improvement in biophysical/biochemical techniques available to study RNA. As for protein targets, genome sequencing is greatly accelerating the identification of human and microbial RNA transcripts for targeted drug discovery. With this explosion in the number of potential RNA and RNP targets, the effective development of specific small molecule RNA-based drugs requires robust and general approaches for detecting and quantifying RNA-ligand interactions, which can be used as high-throughput screens (HTS) and for obtaining rapid structural information to guide rational drug design. In this review, an overview of the potential for therapeutic intervention based on RNA and RNP targets is presented, together with recent efforts to develop generally useful nuclear magnetic resonance (NMR) and fluorescence binding assays for screening and optimizing drugs aimed at RNA and RNP targets.

Current practices in generation of small molecule new leads.

The current drug discovery processes in many pharmaceutical companies require large and growing collections of high quality lead structures for use in high throughput screening assays. Collections of small molecules with diverse structures and "drug-like" properties have, in the past, been acquired by several means: by archive of previous internal lead optimization efforts, by purchase from compound vendors, and by union of separate collections following company mergers. More recently, many drug discovery companies have established dedicated efforts to effect synthesis by internal and/or outsourcing efforts of targeted compound libraries for new lead generation. Although high throughput/combinatorial chemistry is an important component in the process of new lead generation, the selection of library designs for synthesis and the subsequent design of library members has evolved to a new level of challenge and importance. The potential benefits of screening multiple small molecule compound library designs against multiple biological targets offers substantial opportunity to discover new lead structures. Subsequent optimization of such compounds is often accelerated because of the structure-activity relationship (SAR) information encoded in these lead generation libraries. Lead optimization is often facilitated due to the ready applicability of high-throughput chemistry (HTC) methods for follow-up synthesis. Some of the strategies, trends, and critical issues central to the success of lead generation processes are discussed below.

Effects of the 5-HT2C agonist, RO 60-0175, on the antidepressant drug action in the mouse forced swimming test

Computer-aided drug design (CADD) comprises a broad range of theoretical and computational approaches that are part of modern drug discovery. CADD methods have made key contributions to the development of drugs that are in clinical use or in clinical trials. Such methods have emerged and evolved along with experimental approaches used in drug design. In this chapter we discuss the major CADD methods and examples of recent applications to drugs that have advanced in clinical trials or that have been approved for clinical use. We also comment on representative trends in current drug discovery that are shaping the development of novel methods, such as computer-aided drug repurposing. Similarly we present emerging concepts and technologies in molecular modeling and chemoinformatics. Furthermore, this chapter discusses the authors’ point of view of the challenges of traditional and novel CADD methods to increase their positive impact in drug discovery.

HTS in the new millennium: The role of pharmacology and flexibility

Over the past decade, high throughput screening (HTS) has become the focal point for discovery programs within the pharmaceutical industry. The role of this discipline has been and remains the rapid and efficient identification of lead chemical matter within chemical libraries for therapeutics development. Recent advances in molecular and computational biology, i.e., genomic sequencing and bioinformatics, have resulted in the announcement of publication of the first draft of the human genome. While much work remains before a complete and accurate genomic map will be available, there can be no doubt that the number of potential therapeutic intervention points will increase dramatically, thereby increasing the workload of early discovery groups. One current drug discovery paradigm integrates genomics, protein biosciences and HTS in establishing what the authors refer to as the “gene-to-screen” process. Adoption of the “gene-to-screen” paradigm results in a dramatic increase in the efficiency of the process of converting a novel gene coding for a putative enzymatic or receptor function into a robust and pharmacologically relevant high throughput screen. This article details aspects of the identification of lead chemical matter from HTS. Topics discussed include portfolio composition (molecular targets amenable to small molecule drug discovery), screening file content, assay formats and plating densities, and the impact of instrumentation on the ability of HTS to identify lead chemical matter.

The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains

Acommon focus among molecular and cellular biologists is the identification of proteins that interact with each other. Yeast two-hybrid, cDNA expression library screening, and coimmunoprecipitation experiments are powerful methods for identifying novel proteins that bind to one's favorite protein for the purpose of learning more regarding its cellular function. These same techniques, coupled with truncation and mutagenesis experiments, have been used to define the region of interaction between pairs of proteins. One conclusion from this work is that many interactions occur over short regions, often less than 10 amino acids in length within one protein. For example, mapping studies and 3-dimensional analyses of antigen-antibody interactions have revealed that epitopes are typically 4-7 residues long (1). Other examples include protein-interaction modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding domains (PTB), postsynaptic density/disc-large/ZO1 (PDZ) domains, WW domains, Eps15 homology (EH) domains, and 14-3-3 proteins that typically recognize linear regions of 3-9 amino acids. Each of these domains has been the subject of recent reviews published elsewhere (2 3 4 5 6 7). Among the primary structures of many ligands for protein-protein interactions, the amino acid proline is critical. In particular, SH3, WW, and several new protein-interaction domains prefer ligand sequences that are proline-rich. In addition, even though ligands for EH domains and 14-3-3 domains are not proline-rich, they do include a single proline residue. This review highlights the analysis of those protein-protein interactions that involve proline residues, the biochemistry of proline, and current drug discovery efforts based on proline peptidomimetics.-Kay, B. K., Williamson, M. P., Sudol, M. The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains.

Alzheimer's disease and its management in the year 2010.

By 2010 the number of cases of Alzheimer's disease and other dementias will have increased by at least 25 percent. Alzheimer's disease poses an enormous threat to health service and public health resources. Three areas that require targeted research are early detection and recognition, biological markers and diagnosis, and pharmacotherapy. Care of patients with Alzheimer's disease in managed care organizations must be improved through a combination of research, education, advocacy, and legislation. Research in the pathogenic cascade of events within the brain leading to Alzheimer's disease has advanced, and treatment targets within the steps of the process have been specified. The current drug discovery and testing infrastructure is insufficient for major advances in therapy by 2010. Strategies for achieving an optimum outcome by then include increased funding of targeted research; expansion of drug discovery and therapeutic testing efforts; increased training of basic, clinical, and translational scientists; and study of optimum health care delivery systems.

Rho Chi lecture. Pharmaceutical sciences in the next millennium.

Even a cursory survey of this article suggests that the pharmaceutical sciences are being rapidly transformed under the influence of both the new technologies and sciences and the economic imperatives. Of particular importance are scientific and technological advances that may greatly accelerate the critical process of discovery. The possibility of a drug discovery process built around the principles of directed diversity, self-reproduction, evolution, and self-targeting suggests a new paradigm of lead discovery, one based quite directly on the paradigms of molecular biology. Coupled with the principles of nanotechnology, we may contemplate miniature molecular machines containing directed drug factories, circulating the body and capable of self-targeting against defective cells and pathways -- the ultimate "drug delivery machine." However, science and technology are not the only factors that will transform the pharmaceutical sciences in the next century. The necessary reductions in the costs of drug discovery brought about by the rapidly increasing costs of the current drug discovery paradigms means that efforts to decrease the discovery phase and to make drug development part of drug discovery will become increasingly important. This is likely to involve increasing numbers of "alliances," as well as the creation of pharmaceutical research cells -- highly mobile and entrepreneurial groups within or outside of a pharmaceutical company that are formed to carry out specific discovery processes. Some of these will be in the biotechnology industry, but an increasing number will be in universities. The linear process from basic science to applied technology that has been the Western model since Vannevar Bush's Science: The Endless Frontier has probably never been particularly linear and, in any event, is likely to be rapidly supplanted by models where science, scientific development, and technology are more intimately linked. The pharmaceutical sciences have always been an example of use-directed basic research, but the relationships between the pharmaceutical industry, small and large, and the universities seems likely to become increasingly developed in the next century. This may serve as a significant catalyst for the continued transformation of universities into the "knowledge factories" of the 21st century. Regardless, we may expect to see major changes in the research organizational structure in the pharmaceutical sciences even as pharmaceutical companies enjoy record prosperity. And this is in anticipation of tough times to come.

From genome to drug--optimising the drug discovery process.

Current drug discovery and development practices are technologically sophisticated and highly efficient. At the same time the failure rate of compounds in both preclinical and clinical development is high. These failures can be attributed to many factors. Two predominant causes of failure are lack of efficacy and toxicity. Often lack of efficacy is only determined late in the clinical trial process and can be difficult if not impossible to explain, as well as being expensive. Toxicity accounts for many failures during preclinical development, which are less costly, but it also occurs in the clinic. Often the underlying cause of clinical toxicity is never identified. Studies of the structure and activity of the human and other genomes has over the last decade lead to a revolution in biological and medical research. Disease associated genes can now be identified through the application of human genetics, whole genomes have been sequenced and tools have been developed that allow the complete characterization of an organism's gene expression profile in a single experiment. These tools are now being applied to pharmaceutical research and development with the aim to increase the efficiency of the process and the quality of the product.

New Platinum Agents

Compared with most solid tumours in humans, ovarian cancer may be considered a relatively chemosensitive disease. The platinum-based drug, cisplatin, has significantly enhanced long term survival (by more than 10%), though there remains scope for considerable improvement. Carboplatin is equiactive with, but substantially less toxic than, cisplatin (especially in terms of nephrotoxicity, effects on the gastrointestinal tract and neurotoxicity). Long term data are emerging from randomised trials that support the replacement of cisplatin by carboplatin in the first-line treatment of ovarian cancer. Iproplatin is also less toxic than cisplatin, but is more toxic and less active than carboplatin. A further advance in reducing patient morbidity associated with platinum-based chemotherapy may come from the first orally administrable platinum complex, JM216, which has recently been introduced into clinical trials. Current and future platinum drug discovery initiatives should focus on circumventing mechanisms of tumour resistance to cisplatin. Laboratory studies have identified 3 major mechanisms of resistance: reduced drug transport, enhanced intracellular detoxification (through glutathione and/or metallothioneins) and enhanced DNA removal (or tolerance) of platinum-DNA adducts (the long assumed critical lesions leading to cell kill). Platinum complexes based on the 1,2-diaminocyclohexane carrier ligand (such as oxaliplatin and tetraplatin) have recently entered clinical trials, having been shown to circumvent cisplatin resistance in murine leukaemia tumour models. Clinically, they have shown little evidence of activity in cisplatin-resistant disease and appear to cause severe neurotoxicity.