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Latest issue / 13 December 2011 / Andrew A. Parsons, Vice President Preclinical Drug Development, GlaxoSmithKline and Steve Street, Vice President, Head of Research Centres of Emphasis, Head of WRD Continuous Improvement, Pfizer and William Strohl, Vice President of Biologics Research, Centocor R&D, a division of Johnson & Johnson Pharmaceutical Research & Development and Eckhard von Keutz, Senior Vice President, Head Global Early Development, Bayer HealthCare
Andrew A. Parsons, Vice President Preclinical Drug Development, GlaxoSmithKline
Dr. Parsons has led the Preclinical Development function in the CEDD since its creation. He was previously the Head of Preclinical Development for the Neurology and Gastrointestinal (NGI) Center of Excellence for Drug Discovery (CEDD) and a member of the Executive Leadership Team. Dr. Parsons joined SmithKline Beecham in 1991 as a lead biologist on the Migraine Program and played a key role in the identification and development of Frovatriptan and Tonabersat. He has worked in a number of therapy areas within drug discovery and has led teams that progressed numerous compounds in development. He was also previously the Chairman of the Imitrex (Sumatriptan) International Scientific Advisory Board. Dr. Parsons graduated with a BSc, MSc and PhD in Pharmacology, University of Manchester and is a qualified NLP practitioner and Cognitive Therapist. He worked as a post-doctoral researcher at the Institute of Physiology, University of Munich, Germany. He has authored more than 90 peer-reviewed publications.
Steve Street, Vice President, Head of Research Centres of Emphasis, Head of WRD Continuous Improvement, Pfizer
Steve Street joined Pfizer in 1985 and held a variety of roles within the Chemistry Department in Sandwich UK, before being appointed Head of Chemistry for Sandwich Discovery in 2001. Three years later, at the start of 2004, Steve moved to establish and lead the Chemistry discipline across Worldwide Discovery. Steve held this role through to early 2007 when he was delighted to be asked to take on a new role as Head of the Research Centers of Emphasis, covering a range of activities supporting Worldwide Research including External Research, BioImaging, Computational Sciences and High Throughput Screening. In April 2008, Steve was asked to become Head of Continuous Improvement across all of Pfizer Worldwide Research and Development where his focus was uniquely on improving project and portfolio survival and cycle times. (more…)
Latest issue / 13 December 2011 / Henri Xhaard, Head of Computational Drug Discovery Group, Centre for Drug Research, University of Helsinki
The central location of G protein-coupled receptors (GPCRs) at the interface between the interior and exterior of cells, as well as their key role in signalling events, make GPCRs a prominent class of pharmaceutical targets. To date, approximately 40 per cent of known drugs are thought to act on GPCRs either directly or indirectly. GPCRs are for the most part inaccessible to structural determination due to difficulties to express, purify and crystallise them; however, progress of structure determination has led to seven new structures in the last decade. This number is still insufficient to conduct structure-based drug discovery on all available targets. Computational modelling is therefore a very useful surrogate and in this paper I discuss the reliability of atomistic three-dimensional models that are obtained through molecular modelling in light of the GPCRdock 2008 and 2010 competitions organised by the Scripps Institute.
G protein coupled receptors (GPCRs) are key proteins involved in signalling and as such are prominent drug targets1. Ligands that bind to GPCRs include small aminergic neuro – transmitters or hormones such as noradrenaline and adrenaline, dopamine, histamine, small peptides, nucleic acids, lipids or even opsins that contain light-reactive retinal chromophores. Altogether, in the human genome project, about 390 non-olfactory GPCRs have been identified; of which about 100 are orphan proteins without an identified ligand or cellular function. (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…)
Latest issue / 13 December 2011 / Nalini A.L. Mehta & David J. Dow, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline and Anthony M. Battram, Molecular and Cellular Technologies, Platform Technology and Science, GlaxoSmithKline & Department of Life Sciences, Imperial College London
In recent years, the development of Next Generation DNA Sequencing (NGS) technology has significantly impacted molecular biology research, resulting in many new insights and discoveries. NGS technology goes beyond traditional DNA sequencing with applications that reach across the central dogma of molecular biology from DNA to RNA and protein science. Drug discovery is beginning to benefit from the diversity of NGS, with applications in evidence across various therapeutic areas, such as oncology, immunology and infectious diseases.
DNA is the molecule of life, containing the information for the synthesis of RNA molecules and proteins, which in turn form structural components of the cell or catalyse essential biochemical processes. Understanding the sequence of DNA, which is made from the four basic building blocks or ‘nucleotides’, A,G,C and T, has resulted in great insights and discoveries in cellular biology, pathology and disease, culminating in the human genome project, which achieved the remarkable feat of determining the sequence of the three billion bases of the human genome.
The field of DNA sequencing has witnessed some key milestones in technology develop – ment since the description of the first revolutionary DNA sequencing techniques in 19771,2. The Sanger dideoxy sequencing method, discovered by the Nobel Laureate Fred Sanger, underwent the most significant improvements and became the first automated sequencing platform in the late 20th century. Advancements in the Sanger process were partly motivated by the advent of the USD 3 billion Human Genome Project, which required the development of high-throughput tech – niques3,4 (Figure 1A). (more…)
Issue 5 2011 / 19 October 2011 / Brendan Prideaux, Dieter Staab, Gregory Morandi, Nicole Ehrhard and Markus Stoeckli, Novartis Institutes for BioMedical Research
Since its introduction in the field of biomedical imaging over 10 years ago1, matrixassisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) has played an ever increasing role in drug discovery and development and is now utilised in laboratories of many leading pharmaceutical companies and collaborating academic institutions.
The need for mass spectrometry imaging in drug discovery is founded on the shortcomings of current technologies. Traditional methods of spatially mapping the distribution of compounds in tissue involved a combination approach of autoradiography (WBA) with metabolite information obtained from LC/MS analysis of tissue homogenate2. Autoradio – graphy methods only monitor the radiolabel and therefore are not able to distinguish the parent drug from its metabolites. The addition of LC/MS allows for conclusive determination of metabolites. However, this only produces spatial information at the whole organ level and not the spatial detail that can be routinely achieved using MSI. (more…)
Issue 4 2011, Supplements / 31 August 2011 / Bhupinder Bhullar (Novartis Pharma AG), Wei Chen (Max Delbrück Center for Mollecular Medicine Berlin-Buch), Stephen A. Haney (Biological Profiling, Applied Quantitative Genotherapeutics, Pfizer Biotechnologies Unit)
NGS powers up drug discovery and healthcare (Bhupinder Bhullar, Novartis Pharma AG)
Impact of novel sequencing technology on transcriptome analysis (Wei Chen, Max Delbrück Center for Mollecular Medicine Berlin-Buch)
Making sense of nonesense (and missense): Bringing the results of recent genetic studies into the drug discovery laboratory (Stephen A. Haney, (more…)
Issue 4 2011 / 31 August 2011 / S. Assi, S. Fergus, J.L. Stair, O. Corazza and F. Schifano, University of Hertfordshire
Designer drugs represent a rapidly expanding phenomenon particularly facilitated by their internet availability. These drugs are continuously emerging as analogues of controlled substances (amfetamine, aminoindane, cathinone, phencyclidine, etc) and once an analogue has been banned, another replacement analogue appears on the market. They are often made in unlicensed laboratories which can result in their poor quality. This highlights the importance of analysing these products through detecting both their identity and purity. However, most of the analysis methods focused on emerging analogues of cathinone and very few studied other newer analogues such as phencyclidine derivatives. This is due partly to the regulations surrounding the analysis, the time consuming analytical procedures and the technical skills involved. Analysis of these designer drugs in the literature included both the identification of drug products and monitoring of the products consistency over a period of time. In all cases, the results showed that these products may contain a range of a single or mixture of components, including a designer drug, a pharmaceutical active agent, an excipient or inorganic material. (more…)
Issue 4 2011 / 31 August 2011 / Geoff Holdgate, AstraZeneca
Recently, there has been renewed interest in using thermodynamic and kinetic data, alongside empirical rules (particularly focused upon cLogP and molecular weight) and guiding metrics such as ligand efficiency and lipophilic ligand efficiency developed for fragments, leads and drugs in order to facilitate the design of compounds with a greater chance of producing successful drugs1. This interest has been assisted both by improvements in instrumentation as well as evidence that thermodynamically and kinetically optimised compounds fare better in the clinic2.
Optimisation of the binding affinity, which may have to be improved by several orders of magnitude from initial hit to drug molecule, can be achieved by modifying the individual thermodynamic and kinetic contributions. However, medicinal chemists have, up to now, been reluctant to consider these measurements during hit selection and lead optimisation, because it has been difficult to understand how the different design strategies affect the individual forces resulting in different thermodynamic and kinetic profiles. By incorporating both retrospective analysis and real time data collection in active projects, the value of using these fundamental contributions to guide the selection of chemical start points and how they can be used to influence optimisation strategies will become clear. (more…)
Issue 1 2011 / 16 February 2011 / Neil Carragher, Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh
High-content analysis is primed to play a prominent role in a new era of drug discovery research that places greater emphasis on clinical translation at all stages of the discovery process from target identification to proof-of-concept testing. High content analysis provides a technical bridge between reductionist targetdirected drug discovery approaches and new technologies that embrace the biological diversity of human disease.
The drug discovery industry is evolving rapidly, this evolution is stimulated by two key factors; (i) increased accessibility of new technologies such as next generation sequencing, systems biology and imaging that enhance our ability to interrogate complex biological systems and; (ii) the perceived failure of the widely adopted target directed drug discovery operating model to deliver novel medicines. Thus, high content imaging technologies provide a timely, pragmatic solution that enhances the effectiveness of conventional target-directed chemical approaches and provides the necessary biological context for understanding proteomic or genetic signatures. However, the future success of high-content analysis in improving the clinical success rates of drug discovery projects is entirely dependent upon the physiological relevance of the biological models under evaluation. (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 4 2010 / 19 August 2010 / Gül Erdemli & Dmitri Mikhailov, Center for Proteomic Chemistry,
Novartis Institutes for BioMedical Sciences and Albert M Kim,
Translational Medicine, Novartis Institutes for BioMedical Sciences
The preclinical assessment of a small molecule’s liability for QT interval prolongation is an essential part of the drug discovery process. Patch clamp assays for heterologously expressed recombinant cardiac ion channels are widely used in the pharmaceutical industry to evaluate potential drug-channel interactions. These assays are generally acute assessments and are not designed to detect indirect channel modulations that may result in QT prolongation. Despite the abundant literature demonstrating potential transcriptional, translational and post-translational mechanisms for indirect ion channel modulation, contribution of these mechanisms to drug-induced QT prolongation and/or arrhythmia propensity is not well understood. In this brief review, we discuss some potential mechanisms through which indirect ion channel modulation can produce QT prolongation and strategies for their early detection and mitigation. (more…)
Issue 4 2010 / 19 August 2010 / David Cook, Associate Director, Global Safety Assessment, AstraZeneca
Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction which accounts for a significant amount of patient suffering, including death. Currently, idiosyncratic DILI is unpredictable and as a result arises late in the drug development process or even post-marketing. The prediction of idiosyncratic DILI based on preclinical or early clinical data is a formidable challenge and this short review will discuss why and how new initiatives in systems biology and dynamic computational simulations can meet this challenge and predict the ‘unpredictable’. (more…)
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