Paradigm Shift In Drug Discovery Research Articles

Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

Computational approaches towards the rational design of drug-like compound libraries.

During the practice of combinatorial chemistry, it has been realized that molecular diversity is not the only essential feature in a synthetically feasible library. In addition, it is of utmost importance to enrich potential libraries with those molecules which could be converted to viable drug candidates. Given the enormous number of potentially synthesizable compounds, there is a need to design a subset of true "drug-like" compounds. In addition, a paradigm shift in drug discovery has resulted in the integration of pharmacokinetic and drug development activities into early stages of lead discovery. In particular, in silico filters are being developed and used to help identify and screen out compounds that are unlikely to become drugs. This paper highlights recent computational approaches towards the design of drug-like compound libraries, in particular, the prediction of drug-likeness in a more general sense as well as intestinal absorption through passive transport, the permeation of the blood-brain barrier and recent developments towards identification of potentially metabolically unstable molecules. Current computational tools for library design allow the incorporation of medicinal chemistry knowledge into library planning by a variety of methods, ranging from the use of privileged building blocks and simple counting of structural properties (e.g. number of hydrogen bonding partners) to relatively complex regression or neural network-based models to explain oral bioavailability and other pharmacokinetic properties by structural features. These tools are being incorporated more frequently into drug design according to the "rule-of-five" which refers to simple descriptors correlated to oral drug absorption. Combining experimental knowledge with effective computational filtering and prediction of various aspects of drug-likeness thus facilitates the rapid and cost-effective elimination of poor candidates prior to synthesis and helps focus attention on interesting molecules.

Upregulation of neurotoxic serine proteases, prothrombin, and protease-activated receptor 1 early after spinal cord injury.

Apoptosis, well-established in development and now also in degenerative disease, occurs with regularity in several cell compartments early after controlled contusion spinal cord injury (SCI). Cell death in astrocytic, microglial, and neuronal populations peaks at 3 days, while oligodendroglial apoptosis is found 10-14 days later. In this regard, the executioners of apoptosis, the caspase proteases, are also activated within 3 days of SCI. On the other hand, serine proteases, which have been shown to initiate apoptosis and activate caspases in culture models, have not been extensively studied in regards to nervous system trauma. As part of an ongoing effort to examine the spectrum of genes that are up- and downregulated in the injured rat spinal cord, we synthesized serine protease family specific primers to take advantage of conserved residues in the charge relay system and the codon preferences of these mammalian genes. These primers were then employed in a modified, family-specific differential mRNA display technique. One specific serine protease gene we found that was upregulated after injury was prothrombin. Qualitative and quantitative RT-PCR techniques indicated that this increase occurred early, already evident at 8 h after injury, and reached a maximum level fourfold above baseline at 24 h. Peak expression for prothrombin mRNA occurred prior to peak levels of apoptosis in astrocytic, microglial and neuronal compartments at 72 h. Of additional interest, gene database mining revealed that prothrombin shared approximately 48% similarity with myelencephalon-specific protease (MSP), a neurotoxic serine protease previously found to be increased two- to threefold at 3 days after excitotoxic SCI. Since thrombin induces apoptosis in murine and chick motor and rat hippocampal neurons by activating a member of the novel protease-activated receptor (PAR) gene family known as PAR-1, we also analyzed PAR-1 by similar techniques and found that it, too, was upregulated after SCI with the same kinetics as prothrombin. We confirmed these results with gene array analyses that revealed more than one trypsin subfamily serine protease was activated by SCI. They imply the possibility of using specific, tissue-directed serine protease inhibition at translational or transcriptional levels, and offer a potential paradigm shift in drug discovery for SCI to limit the extent of apoptosis, and consequent functional loss, in the human spinal cord.

ChemInform Abstract: Parallel Array and Mixture-Based Synthetic Combinatorial Chemistry: Tools for the Next Millennium

Technological advances continue to be a central driving force in the acceleration of the drug discovery process. Combinatorial chemistry methods, developed over the past 15 years, represent a paradigm shift in drug discovery. Initially viewed as a curiosity by the pharmaceutical industry, combinatorial chemistry is now recognized as an essential tool that decreases the time of discovery and increases the throughput of chemical screening by as much as 1000-fold. The use of parallel array synthesis approaches and mixture-based combinatorial libraries for drug discovery is reviewed.

Parallel array and mixture-based synthetic combinatorial chemistry: tools for the next millennium.

Technological advances continue to be a central driving force in the acceleration of the drug discovery process. Combinatorial chemistry methods, developed over the past 15 years, represent a paradigm shift in drug discovery. Initially viewed as a curiosity by the pharmaceutical industry, combinatorial chemistry is now recognized as an essential tool that decreases the time of discovery and increases the throughput of chemical screening by as much as 1000-fold. The use of parallel array synthesis approaches and mixture-based combinatorial libraries for drug discovery is reviewed.