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Latest issue / 13 December 2011 / Ole Pless and Sheraz Gul, European ScreeningPort GmbH
Multiple Sclerosis (MS) is an autoimmune disease leading to a chronic inflammation and degeneration of the central nervous system. It is one of the major neurological diseases with approximately 2.5 million suffering patients worldwide. Until now, the underlying mechanisms have not been fully elucidated, but the cause of the disease can be modulated to limit progression and severity. Currently, there are no validated biomarkers available to predict the progression of MS or response to a clinical intervention apart from MRI. In order to identify protein biomarkers for MS as well as other diseases, significant infrastructure is required and this is discussed.
The term ‘biomarker’ has been defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”1,2. The measurement of normal and dysfunctional biological processes and their changes in response to therapeutic intervention forms the basis of biomarkers. The advances in genetics and molecular biology leading to the sequencing of the human genome has resulted in the identification of a variety of novel targets implicated in different disease states3-5. Further technological developments including high throughput profiling of various samples using genomics, transcriptomics and proteomics6,7 has led to the identification of gene and protein based markers that characterise disease states for a number of indications including breast cancer8-10, colorectal cancer11 and cardiovascular diseases12. Additional initiatives that have led to the identification of biomarkers with minimal invasive methods such as proteomics technologies13 and systems biology14 have proven extremely effective for discovering potential biomarkers and drug targets. These technologies tend to provide large data sets that can be difficult to deconvolute for biomarker discovery. This bottleneck can be reduced by using several strategies. The first is to constrict the number of potential biomarkers and drug targets by dividing the proteome into smaller, more biologically significant segments. The second is to widen the bottleneck with higheroutput and higher-throughput screening technologies. The third is to incorporate more preliminary validation into the discovery process. New and emerging technologies provide promise for each of these strategies15. (more…)
Latest issue / 13 December 2011 / Sheraz Gul, Vice President and Head of Biology, European ScreeningPort GmbH
The pre-clinical phase of drug discovery spans a period in the region of five years and requires contributions from multi-disciplinary teams often working at different sites. These teams can generate significant amounts of data which are processed using standard as well as specialist software. The recording of a substantial amount of project related experimental work has historically been performed using paper-based laboratory notebooks completed manually with all files usually being stored locally.
This scenario poses a variety of issues such as delayed access to important information to the project team members which could ultimately reduce its efficiency and thus increase the time taken to complete the project. These paper-based notebooks are now being replaced by an electronic laboratory notebook (eLNB) within research laboratories in industry and academia. Such software allows the documentation of experimental data and its sharing within the multi-disciplinary research team and would be expected to improve data integrity, reduce the time to complete the project and improve communication. This article discusses some of the advantages that would be expected to be achieved upon implementing an eLNB in pre-clinical drug discovery. (more…)
Issue 3 2011 / 20 June 2011 / Sheraz Gul, Vice President & Head of Biology, European ScreeningPort GmbH
The development of most diseases is often attributed to the dysfunction of the activities of key proteins involved in biological processes and their modulation by a therapeutic agent is considered to offer the potential to alleviate the disease state. However, prior to discovering a therapeutic agent, it is usually necessary to identify and validate that a particular protein is the underlying cause of the disease. It is often the case that a single target is implicated as being the cause of more than one disease. This suggests that particular focus needs to be paid to validating these targets for drug discovery purposes as many experimental drugs that are designed to modulate the activity of a specific protein often fail to exhibit efficacy during clinical trials. The role that biomarkers can play in reducing the attrition observed in drug discovery will be discussed in this article. (more…)
Issue 1 2011 / 16 February 2011 / Sheraz Gul, Vice President & Head of Biology, European ScreeningPort GmbH
Although many of the marketed small molecule drugs have been discovered by research and development efforts within the pharmaceutical industry, there has been a paradigm shift with external sources increasingly being relied upon to fill their pipelines. This trend is likely to increase and the key pre-clinical activities carried out by organisations outside the pharmaceutical industry include target validation, assay development and their use in High Throughput Screening campaigns, validation of the Hit molecules, Hit-to-Lead and Lead-to-Candidate screening/chemistry. In order to perform these activities, adequate know-how and technical expertise is essential so that the processes meet appropriate industry standards. This article discusses some of the challenges associated with assay development and the automation of High Throughput Screening. (more…)
Issue 2 2010 / 9 May 2010 / Sheraz Gul, Vice President, European ScreeningPort GmbH
In this article, an overview regarding advances in assay formats for specific target classes and options that should be considered when considering hardware will be given. There has been a significant growth in the assay and automation technologies that are available for compound screening activities and it is essential to evaluate a variety of these before beginning a drug discovery program, the aims of these being to ensure the most relevant assay formats that are available are adopted. (more…)
Industry Focus 2010, Past issues / 22 February 2010 /
Over the past decade we have seen a significant realignment of activities associated with drug discovery and this will continue for a multitude of reasons. Within the pharmaceutical industry we have seen significant changes e.g. a decrease in the numbers of drugs that are being approved by the regulatory authorities and the looming expiration of patented drugs, both of which have an immediate and direct consequence on revenue streams. In light of these issues, the pharmaceutical industry is responding appropriately. These changes have included a re-assessment of the strategies being employed in the pre-clinical phase of drug discovery, some of which are discussed in relation to automation solutions. (more…)
Issue 6 2009, Past issues / 12 December 2009 /
Dr Gordon R Alton, Dr Scott Bowes, Dr Sheraz Gul and Chris Molloy discuss Lab Automation in this European Pharmaceutical Review roundtable discussion. (more…)
Issue 2 2009, Past issues / 20 March 2009 /
There has been a continuous move by the large commercially orientated players involved in Drug Discovery to initiate novel methods to increase income streams and productivity. An example of the former has been the acquisition of companies and their drug pipelines and in the case of the latter, rationalisation of internal Research & Development activities. This is well illustrated by GlaxoSmithKline Pharmaceuticals which have formed small focused research units called the Centres for Excellence in Drug Discovery (CEDD) and the Discovery Performance Units (DPU) each of which having increased accountability1.
Many of the small molecule entities discovered in the pre-clinical phases of Drug Discovery have been identified from compound screening activities (CSA) e.g. Low Throughput Screening (LTS) usually employing focussed sets of compounds (numbering in the low tens of thousands) and High Throughput Screening (HTS) utilising significantly larger libraries (in the hundreds of thousands and in some cases in the region of one million compounds)2-5. These CSA require two inputs, namely an assay and high quality compound library. Up until relatively recently, most of the microtitre plate based CSA were carried out in an in vitro biochemical format that used targets in a purified form (tagged truncate or full length) prepared from recombinant expression systems. Crude preparations will also suffice, however, appropriate control experiments are required to ensure the measured modulation of target activity in the presence of compound is not due to a contaminant within the preparation. Of course, assays for transporters, ion-channels, and receptors would be in a cell membrane or cellular system. These in vitro biochemical assays tend to be a context far removed from actual physiological conditions6. More recently, human primary and stem cell based assays are becoming more common in CSA7-9. In order to enhance the outputs from these assays, High Content Screening (HCS) can also be used to yield phenotypic read-outs (e.g. changes in morphology, sub-cellular localisation and redistribution of proteins)10. The second component required for CSA, the high quality compound library, would be expected to contain known scaffolds (for LTS) or diverse chemical space (for HTS) that contain appropriate starting points for Drug Discovery. (more…)
Issue 6 2008, Past issues / 3 December 2008 /
High Throughput Screening (HTS) has for many years now been playing a central role in drug discovery efforts to aid the identification of small molecule chemical entities that are capable of modifying the activity of disease relevant targets1. In order to make HTS a viable option to provide appropriate starting points for drug discovery efforts, large libraries of compounds are required that contain diverse chemical space.
These libraries are typically composed of 0.5 to 3.0 million distinct compounds in solution (usually DMSO) of which 10,000 to 100,000 are available in solid form. Subsequent to the execution of an HTS at an appropriate single concentration of compound, thousands of these are typically identified and are classified as actives. Some of these initial actives may be false positives, therefore their activities are usually confirmed in independent experiments carried out in duplicate followed by dose-response experiments to determine their potencies. The final set of confirmed actives is termed validated hits. Appropriate selectivity and liability assays enables annotation of these compounds and the most promising ones can be considered for structure-activity-relationship (SAR) studies. The SAR process is an iterative process in which new compounds are synthesised, their activities determined in appropriate assays, followed by further synthesis and compound profiling. Upon achieving the desired properties in the compound, potential starting points (lead like molecules) are obtained which would undergo a series of in-vivo validation studies. Subsequent lead optimisation could result in a pre-clinical candidate molecule which would enter a period of efficacy, safety and absorption, distribution, metabolism, excretion and toxicity (ADME-Tox)2 testing in animals and ultimately enter the various human clinical studies. The time period for a drug discovery program from its conception to initiation of human clinical trials is typically in excess of five years and consumes tens of millions of dollars. This article will overview how liquid handling technologies have aided the successful development of screening compatible assays. (more…)
Issue 5 2008, Past issues / 29 September 2008 /
An issue that the drug discovery industry has faced over the past several years has been that whilst the number of targets in their portfolios has increased and the level of investment across all Research & Development functions has risen, the likelihood of discovering suitable chemical starting points for medicinal chemistry efforts has remained static1.
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