Novel Trends in High-Throughput Screening

High-throughput screening (HTS) is a well established process for lead discovery in Pharma and Biotech companies and is now also being used for basic and applied research in academia. .It comprises the screening of large chemical libraries for activity against biological targets via the use of automation, miniaturized assays and large-scale data analysis. Since its first advent in the early to mid 90’s, the field of HTS has seen not only a continuous change in technology and processes, but also an adaptation to various needs in lead discovery. HTS has now evolved into a mature discipline that is a critical source of chemical starting points for drug discovery. Whereas in previous years much emphasis has been put on a steady increase in screening capacity (“quantitative increase”) via automation and miniaturization, the last years have seen a much greater emphasis on content and quality (“quality increase”). Today, many experts in the field see HTS at a crossroad with the need to decide on either higher throughput/more experimentation, or a greater focus on assays of greater physiological relevance, both of which may lead to higher productivity in pharmaceutical R&D. In this paper, we describe the development of HTS over the last decade and point out our own ideas for future directions of HTS in biomedical research. We predict that the trend towards further miniaturization will slow down with the balanced implementation of 384-well, 1536-well and 384 low-volume-well plates. Furthermore, we envisage that there will be much more emphasis on rigorous assay and chemical characterization, particularly considering that novel and more difficult target classes will be pursued. In recent years we have witnessed a clear trend in the drug discovery community towards rigid hit validation by the use of orthogonal readout technologies, label-free and biophysical methodologies. We also see a trend towards a more flexible use of the various screening approaches in lead discovery, i.e. the use of both full deck compound screening as well as the use of focused screening and iterative screening approaches. Moreover, we expect greater usage of target identification strategies downstream of phenotypic screening and the more effective implementation of affinity selection technologies as a result of advances in chemical diversity methodologies. We predict that, ultimately, each hit finding strategy will be much more project-related, tailor-made and better integrated into the broader drug discovery efforts

Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety.

The drastic increase in the costs for discovering and developing a new drug and the high attrition rate of development candidates led to shifting of drug discovery strategy to parallel assessment of comprehensive drug properties along with efficacy. The article reviews the benefits and caveats of implementing comprehensive in vitro tools in early drug discovery and their impact on addressing in vivo ADMET issues. With the proposal of four-barrier profiling paradigm and employment of integrated risk assessment, one can exponentially enhance the predictive power of those in vitro tools by taking into consideration the interplays among those profiling parameters. An 'Exposure Cube' is proposed to promote collective employment of solubility/dissolution, permeability and metabolic clearance to address in vivo exposure and to direct optimization of new chemical entities in drug discovery

Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development.

Broad-scale in vitro pharmacology profiling of new chemical entities during early phases of drug discovery has recently become an essential tool to predict clinical adverse effects. Modern, relatively inexpensive assay technologies and rapidly expanding knowledge about G-protein coupled receptors, nuclear receptors, ion channels and enzymes have made it possible to implement a large number of assays addressing possible clinical liabilities. Together with other in vitro assays focusing on toxicology and bioavailability, they provide a powerful tool to aid drug development. In this article, we review the development of this tool for drug discovery, its appropriate use and predictive value