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Drug discovery - Articles and news items
TRV027 is a biased ligand; the in vitro profile and its translation into in vivo pharmacology is discussed during this webinar.
Industry news / 8 January 2015 / Oxford Global Conferences
Oxford Global Conferences were proud to present the Drug Discovery USA Congress this October in Boston, USA…
Issue 6 2014 / 23 December 2014 / Paul McCracken & Stephen Krause
In this review, we highlight a few of the ways in which Eisai is attempting to address the research and development bottleneck by adding fit-for-purpose imaging biomarkers to discovery and early development programs for decision making…
Presented by Dr Elad Katz, a senior scientist at AMSBIO, a new on-demand webinar explores the potential of 3D cell-based models for regenerative medicine and drug discovery…
Proteases: How naturally occurring inhibitors can facilitate small molecule drug discovery for cysteine proteases
Cysteine proteases are expressed ubiquitously in the animal and plant kingdom and are thought to play key roles in maintaining homeostasis. The aberrant function of cysteine proteases in humans are known to lead to a variety of epidermal disease states such as inflammatory skin disease. In marked contrast, the serine proteases have been most widely implicated in disease states, including hypertension, periodontisis, AIDS, thrombosis, respiratory disease, pancreatitis and cancer, and a number of their inhibitors have been approved for clinical use.
Raman spectroscopy has emerged as the preeminent analytical tool for a number of applications within drug discovery and development. Advances in the instrumentation, sensor fabrication and data analysis have enabled the wider acceptance of Raman spectroscopy. In discovery, Raman spectroscopy is used to elucidate structural activity relationships and to optimise reaction conditions and associated parameters (such as polymorph and formulation screening) that impact scale-up required for the transfer of drug compounds from discovery to development.
G protein-coupled receptors are one of the major classes of therapeutic targets for a broad range of diseases. The most commonly used assays in GPCR drug discovery measure production of second messengers such as cAMP or IP3 that are the result of activation of individual signalling pathways. Such specific assays are unable to provide a holistic view of the cell response after GPCR activation. This is now changing as label-free technologies and assays on whole cells have been developed that are unbiased towards the specific downstream pathways and capture the integrated cell response. In this mini-review, we focus on the application of one of these technologies, namely resonant waveguide grating (RWG) for measurements of dynamic mass redistribution (DMR) in intact cells upon GPCR activation. Since the technology is sensitive and non-invasive, it is applicable to most cell types, including primary cells with native receptor expression levels. We discuss how DMR assays have become an important component of GPCR drug discovery screening cascades and may have the potential to improve the ability to predict if compounds will be efficacious in vivo.
Torrey Pines Institute for Molecular Studies and InvivoSciences collaborate to accelerate drug discovery in cardiac disease…
The average cost to a major pharmaceutical company of developing a new drug is over USD 6 billion. Herper observes that the pharmaceutical industry is gripped by rising failure rates and costs, and suggests that the cost of new drugs will be reduced by new technologies and deeper understanding of biology. While the objectives of drug discovery don’t change, the methods and techniques by which pharmaceutical companies, biotechs and academia discover new drugs are evolving at a significant pace – and they need to. Drug discovery scientists are all aiming to identify compounds and candidate drugs with ‘good’ properties that are safe and efficacious, as quickly and cheaply as possible. The standard approach of the last 20 years has been to identify a single molecule disease target, and then to identify a compound that interacts with and modulates this target with high specificity. However, there is now a growing realisation that this ‘one target – one drug’ approach doesn’t work well, and that screening huge libraries of compounds against one particular property of an isolated target is an inefficient way to discover potential drugs. Much of the innovation currently seen in drug discovery methodologies seeks to access and integrate more information – about targets, compounds, and disease phenotypes – to enable a more comprehensive and holistic approach to discovering ‘good’ drug candidates. This article does not try to crystal ball-gaze deep into the future, but rather to identify those trends in the adoption of new technologies and approaches that are gaining traction now, and that can be expected to become more prevalent in the next two to three years…
Drug Discovery, Issue 6 2012 / 18 December 2012 / D. Lansing Taylor, Director, University of Pittsburgh Drug Discovery Institute and Allegheny Foundation Professor of Computational and Systems Biology, University of Pittsburgh School of Medicine
The pharmaceutical industry has experienced a decade of turbulence driven by the ‘patent cliff’ as major revenue generators are lost to generic status, coupled to the absence of a sustainable pipeline of drug candidates in development that have a good chance of being approved and launched. It is generally agreed that the lowest hanging drug discovery ‘fruit’ has been harvested and the industry is addressing diseases that are more complex. The current one target, one drug discovery and development paradigm continues to exhibit more than 90 per cent attrition mainly due to the lack of success in translating preclinical efficacy and safety data into successful human trials. It has also become clear that efficient drug discovery and development requires a deeper understanding of the complexity of human biology early in the process. The high attrition rates increase the costs and with the science indicating that precision therapeutics will replace the blockbuster model, the challenge of drug discovery and development is even greater. The traditional business model of pharmaceutical companies working in silos is no longer sustainable…
In the journey of a molecule from its origins in a compound library to candidate drug status, a large variety of profiling must occur to define activity, selectivity, potency, adverse effects, pharmacology and in vivo efficacy. Advances in biophysical methods that can analyse drug interactions with a molecular target, a whole cell, or even ex vivo tissue have enabled many of these studies to be carried out without the need for reporter-based or ‘labelled’ assays. Label-free screening in high-throughput mode can be used as a pathway independent screening tool with whole cells, or in low-throughput mode with individual receptors to define interaction kinetics and thermodynamics. We highlight advances in optical and impedance-based biosensors, and examine their utility and suitability for various stages of the drug discovery process.
In the early to mid 20th century, drug discovery was a far more productive industry, and more drugs were launched per Pharma employee than today. The regulatory pathway that pre-empted the launch of a new drug was concise and easy to understand, and applications were dealt with expeditiously with a fraction of the supporting data required today. The process of discovery was also very different; it was driven largely by individuals in small teams who were prepared for serendipity, or by individuals with a very clear, defined hypothesis who drove rational drug design. Screening technologies could be summed up on one or two pages of a review; a dozen or so primary assays, some basic biochemistry to define ligand mode of action, perhaps some live cell work and a proof of concept demonstration in vivo…
The histone deacetylase (HDAC) class of enzyme are a group of conserved enzymes known for their ability to remove acetyl groups from lysine residues on histone tails. Since aberrant HDAC enzyme expression is observed in various diseases, there is increasing interest in finding small molecules which function as HDAC enzyme inhibitors. This article reviews the various biochemical assays available for monitoring HDAC enzyme activity that have been validated for use in High Throughput Screening. The assays referred to are compatible with standard microtitre plates (96 and 384 well format) and make use of absorbance, luminescence and fluorescence detection methods.
The histone deacetylase class of enzymes: The histone deacetylase (HDAC) class of enzymes are involved in many biological pathways and one of their best known properties is their ability to remove acetyl groups from lysine residues on amino-terminal histone tails. Thus far, 18 HDAC enzymes have been identified which are divided into zinc dependent and NAD dependent enzymes. The Class I HDAC enzymes include the zinc dependent HDACs 1, 2, 3, and 8 and consist of 350-500 amino acid residues. The Class II HDAC enzymes are also zinc dependent but are larger, consist of about 1,000 amino acid residues and are subdivided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and HDAC10) enzymes. The Class I and Class II HDAC enzymes can be inhibited by trichostatin A (TSA) and this inhibitor is often used as a reference to bench-mark their assays. The Class III HDAC enzymes are the sirtuin enzymes (SIRT1-7) and are NAD-dependent. This class of enzymes is not sensitive to TSA but can be inhibited for example by nicotinamide.
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