Drug discovery - Articles and news items

Thermodynamics and kinetics driving quality in drug discovery

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…)

Advancing high content analysis towards improving clinical efficacy

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…)

Establishing assays and small molecule screening facilities for Drug discovery programs

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…)

Indirect modulation of cardiac ion channels and implications for preclinical safety assessment

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…)

Applying systems biology and computer simulations to predicting idiosyncratic DILI

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…)

Applying automation in early drug discovery: lessons learnt and future perspectives

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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Europe’s premier event for Drug Discovery

Issue 5 2008, Past issues / 29 September 2008 /

This year’s Leading European Event for Drug Discovery – MipTec 2008 – moves from spring to autumn and will be held on the 14-16 October 2008 at the Congress Centre Basel, Switzerland.

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High throughput materials discovery “reducing product time to market”

Issue 1 2008, Past issues / 23 January 2008 /

With ever mounting market pressure on industries, from increasing global competition, along with consumer desire for value for money and improved performance results there is a greater driving force to stay one step ahead by reducing product time to market. This enforced impetus has many companies having to continually improve existing formulations and launch new products in order to expand their product portfolio and market share.

Although the use of automation to accelerate product development and reduce research bottle-necks is already well established in the pharmaceutical, bio-technology and catalysis industries, Automation in many other large industries, especially in the area of materials research, is still largely under-utilised and many processes are still performed manually.

There are a great number of benefits from using high throughput equipment and research methodologies to an organisation that chooses to implement them. The more apparent advantages are accelerated sample throughput, leading to reduced project time and cost which enables companies to compete more efficiently. It also provides the opportunity to map out a larger experimental space than possible with manual approaches, allowing the organisation to tackle research tasks previously thought to be beyond their capabilities and therefore letting them broaden their product patent coverage. Also, one of the less acknowledged benefits of the use of high throughput techniques is the “faster-to-no” result which allows companies to perform more speculative research and to rapidly identify and terminate unsuccessful projects. (more…)

Driving lab automation forward

Issue 6 2007, Past issues / 23 November 2007 /

A round table discussion covering the driving forces behind the integration of automated technology within the pharmaceutical industry, the procedures that are followed when implementing new automated techniques, current areas of drug discovery most benefiting from lab automation, how lab automation advanced the drug discovery marketplace over the last five years, the groundbreaking techniques occurring in lab automation, the relationship between vendor companies and their customers and the current limitations within lab automation. (more…)

Automated workflow optimisation and assay development strategies for High Content Research Facility, Trinity College Dublin

Issue 6 2007, Past issues / 23 November 2007 /

High Content Screening (HCS) is becoming increasingly utilised as an early drug-discovery and basic research tool for defining the functions of genes, proteins and other biomolecules in normal and abnormal cellular functions. HCS involves the integration of a number of preparation steps which include; cell-sample preparation, fluorescent labelling, image acquisition, image processing, image analysis, information management and knowledge mining₁.

These advanced microscopy and image analysis platforms are proving to be immensely powerful tools for the study of molecular and morphological events in cells. This allows for the first time, a multi-parametric characterisation of gross cellular responses and behaviour of a variety of molecular and cellular targets, including subcellular localisation and redistribution of individual proteins and complex cellular structures. In contrast to the more traditional biochemical or genetic analysis, HCS allows for the detection of physiological responses within the context of the structural and functional networks of cells in both normal and diseased states₂. (more…)

Protein crystallography in drug design: current bottlenecks

Issue 5 2007, Past issues / 21 September 2007 / Timothy Allison & Sanjeev Munshi, Department of Structural Biology, Merck, Westpoint, PA

Protein crystallography is an integral component of the structure-guided drug discovery process. Rapid access to structural information about drug targets as well as bound ligands has been pivotal in accelerating lead identification and optimisation processes. While automation and robotics have been employed at every stage along the gene-to-structure path, significant challenges remain in increasing successful outcomes and in reduction of timelines. Advances in high through-put technologies to automate protein expression and crystallisation, the two weakest links in the gene-to-structure process chain, are beginning to address these issues. This article will highlight the importance of rapid structure determination of protein-ligand complexes in lead optimisation, and describe recent developments towards overcoming these bottlenecks. (more…)

A new era for microcalorimetry in drug development

Issue 5 2007, Past issues / 21 September 2007 / Dr Ernesto Freire, Faculty Professor, Johns Hopkins University, Baltimore

Drug development involves the identification and subsequent optimisation of low molecular weight compounds with a desired biological activity. Often, the initial binding affinity of those compounds towards their intended target needs to be improved by five or more orders of magnitude before they become viable drug candidates; a process that would be greatly facilitated if the different forces that contribute to binding were experimentally accessible. Isothermal titration calorimetry (ITC) provides such a tool.

Of all the techniques available to measure binding, ITC is the only one capable of measuring not only binding affinities, but also the different thermodynamic forces that determine the binding energy. In the past, however, ITC has been used retrospectively rather than as a guiding tool for lead optimisation. This situation is changing due to two factors: improved understanding of the relationships between thermodynamic forces (enthalpy, entropy and heat capacity) and chemical structure, and a new generation of instruments with reduced sample requirements and much faster throughputs. In this article these developments, which anticipate a new era in microcalorimetry, will be discussed.

Prevalent strategies in drug discovery rely heavily on the screening of large libraries of compounds. Most often, targets for drug development are enzymes and the screening is performed by implementing enzyme inhibition assays in a high throughput format that allows the rapid identification of compounds with inhibitory activity. Usually, compounds identified by screening ‘hits’ have binding affinities in the low to high micromolar range, requiring potency improvements of five or more orders of magnitude before they can become viable drug candidates. Nevertheless, these hits provide the starting material for further development. (more…)