Drug Discovery Technologies Research Articles

Lab-on-a-chip: microfluidics in drug discovery

Miniaturization can expand the capability of existing bioassays, separation technologies and chemical synthesis techniques. Although a reduction in size to the micrometre scale will usually not change the nature of molecular reactions, laws of scale for surface per volume, molecular diffusion and heat transport enable dramatic increases in throughput. Besides the many microwell-plate- or bead-based methods, microfluidic chips have been widely used to provide small volumes and fluid connections and could eventually outperform conventionally used robotic fluid handling. Moreover, completely novel applications without a macroscopic equivalent have recently been developed. This article reviews current and future applications of microfluidics and highlights the potential of 'lab-on-a-chip' technology for drug discovery.

Introduction

Animal models of aging are now a well-established tool for investigating rate-limiting steps in the aging process. Many single gene mutants have been identified in Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster and mice that extend lifespan. By definition, the genetic extension of lifespan implicates these genes in processes that limit lifespan in these organisms. The almost routine identification of such ‘gerontogenes’ has prompted a number of laboratories to search for pharmacological interventions that mimic the effects of manipulating these genetic pathways. These efforts have also been mirrored in the biotech industry, where a number of academic investigators successful in identifying genes that modulate aging have formed companies which aim to produce compounds which extend lifespan, mimicking the effects of ‘gerontogenes’. Hence there is tremendous excitement within the field that insights gained from the genetics of aging in model organisms will ultimately result in the identification of drugs that modulate aging in humans. Insights into mechanisms conserved between species have been gleaned for a number of the gerontogenes identified to date, lending additional credence to the idea that compounds that work in lower order species will have some success in modulating aging in mammals. We therefore convened a meeting to discuss this convergence of ideas entitled ‘Pharmacology of lifespan extension’. Although this is a somewhat bold title (as routine pharmacological extension of lifespan in multiple species is not yet commonplace), we felt the time was right to exchange ideas in an open and constructive fashion and discuss and integrate the approaches for identifying putative agents that modulate aging. On 6–8 October 2005, we brought together investigators from diverse backgrounds such as high throughput drug screening, caloric restriction, stress, and various model systems in which it is trivial to extend lifespan, to facilitate new ideas and discussions with regards to pharmacological interventions in aging itself. It was clear at the meeting that a convergence of approaches was occurring crossing multiple disciplines, focusing on the extension of lifespan via pharmacological interdiction. This was an exciting meeting, and many who attended felt it could herald the birth of a new field. Much remains to be done, however, not least the dissection of mechanistic nuances of how extension of lifespan occurs in model systems, which hopefully will illuminate potential targets for drug design in the extension of lifespan. In addition, there is a vast gulf between the current approaches to identifying life-extending compounds and true high throughput screening technology for drug discovery. What follows is a collection of articles from presenters at the meeting, focusing on approach, regulatory hurdles to be overcome in the introduction of such lifespan-extending agents, as well as potential targets for drugs in both diseases associated with aging, and aging itself. The organizers would like to thank the following for financial support for the meeting: the National Institutes of Health, the Ellison Medical Foundation, Blackwell Publishing, and the Larry L. Hillblom Foundation.

Chips to Hits: microarray and microfluidic technologies for high-throughput analysis and drug discovery

Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Tel.: +1 617 253 3638; Fax: +1 617 258 8827; alik@mit.eduExpert Rev. Mol. Diagn.

Sequence-Based Protein Kinase Inhibition: Applications for Drug Development

Nearly a century ago, Paul Ehrlich proposed his lock and key theory that has remained one of the cornerstones of rational drug development. Disrupting or enhancing the interaction between a ligand and its substrate is the basis for numerous drugs targeting signal transduction processes. Much of drug discovery is based on finding molecular mimics that resemble either the lock or key of a given ligand-substrate pair. The challenge of drug development is the rapid and efficient identification of mimics that are highly selective and specific for the targeted interaction. Scientists associated with Keryx Biopharmaceuticals (New York, NY, USA) have developed two drug discovery technologies, based on molecular mimicry, that combines rapid development of drug candidates and identification of potential biomarker targets for selected indications. KinAce™ is a platform technology for the protein-sequence-based development of small peptide-derived kinase inhibitors developed by Shmuel A. Ben-Sasson at the Hebrew University in Jerusalem and Keryx Biopharmaceuticals (1,2). KinScreen™ is a method for identifying novel target kinases utilizing peptides developed via the KinAce technology. Peptides directed against specific kinases are tested in a series of biomarker assays that serve as in vitro models for a variety of diseases or pathologic processes including cancer, diabetes, angiogenesis, and immune

Triggered Activation and Release of Liposomal Prodrugs and Drugs in Cancer Tissue by Secretory Phospholipase A2

The selectivity of anticancer drugs in targeting the tumour tissue presents a major problem in cancer treatment. In this article we review a new generation of smart liposomal nanocarriers that can be used for enhanced anticancer drug and prodrug delivery to tumours. The liposomes are engineered to be particularly degradable to secretory phospholipase A2 (sPLA2), which is a lipid hydrolyzing enzyme that is significantly upregulated in the extracellular microenvironment of cancer tumours. Thus, when the long circulatory liposomal nanocarriers extravasate and accumulate in the interstitial tumour space, sPLA2 will act as an active trigger resulting in the release of cytotoxic drugs in close vicinity of the target cancer cells. The sPLA2 generated lysolipid and fatty acid hydrolysis products will furthermore be locally released and function as membrane permeability promoters facilitating the intracellular drug uptake. In addition, the liposomal membrane can be composed of a novel class of prodrug lipids that can be converted selectively to active anticancer agents by sPLA2 in the tumour. The integrated drug discovery and delivery technology offers a promising way to rationally design novel tumour activated liposomal nanocarriers for better cancer treatment.

Metabonomics in preclinical drug development

Metabonomics has emerged as a key technology in preclinical drug discovery and development. The technology enables noninvasive systems assessment of untoward effects induced by candidate compounds characterising a broad spectrum of biological responses on an individual animal basis in a relatively rapid-throughput fashion, thus making it an ideal addition to early preclinical safety assessment. However, the implementation and interpretation of the technology and data it generates is not something that should be trivialised. Proper expertise in biological sciences, analytical sciences (nuclear magnetic resonance and/or mass spectrometry) and chemometrics should all be considered necessary prerequisites. If these factors are properly considered, the technology can add significant value as a tool for preclinical toxicologists.

Book Review: Applying Genomic and Proteomic Microarray Technology in Drug Discovery. By Robert S. Matson

Book Review: Applying Genomic and Proteomic Microarray Technology in Drug Discovery. By Robert S. Matson

Statistical Analysis of Systematic Errors in High-Throughput Screening

High-throughput screening (HTS) is an efficient technology for drug discovery. It allows for screening of more than 100,000 compounds a day per screen and requires effective procedures for quality control. The authors have developed a method for evaluating a background surface of an HTS assay; it can be used to correct raw HTS data. This correction is necessary to take into account systematic errors that may affect the procedure of hit selection. The described method allows one to analyze experimental HTS data and determine trends and local fluctuations of the corresponding background surfaces. For an assay with a large number of plates, the deviations of the background surface from a plane are caused by systematic errors. Their influence can be minimized by the subtraction of the systematic background from the raw data. Two experimental HTS assays from the ChemBank database are examined in this article. The systematic error present in these data was estimated and removed from them. It enabled the authors to correct the hit selection procedure for both assays.

Managing Drug Discovery Alliances For Success

OVERVIEW:Although alliances are increasingly important to pharmaceutical companies, about 60 percent of alliances fail to produce their desired outcomes. Most of these failures are due to non-technical reasons. An analysis of Aventis' portfolio of drug discovery technology alliances suggests that addressing the key challenges that alliances pose to large pharmaceutical companies can reduce these failures. Moreover, three lessons emerge from the analysis as a pattern across successful alliances between large pharmaceutical companies and biotechnology firms as well as academia. These lessons provide a tactical basis for managers to implement and manage alliances across the drug discovery value chain.

IBC's 10th Annual World Congress DRUG DISCOVERY TECHNOLOGY AND DEVELOPMENT 2005 Boston, MA, USA August 8–11, 2005

IBC's 10^th Annual World Congress DRUG DISCOVERY TECHNOLOGY AND DEVELOPMENT 2005 Boston, MA, USA August 8–11, 2005

PHARMA COMMUNITY LOOKS TO IMPROVE

THE PHARMACEUTICAL AND biotech research community converged on Boston last week for the 10th annual Drug Discovery Technology conference, sponsored by IBC Life Sciences. Much of the discussion at c...

10th Anniversary DRUG DISCOVERY TECHNOLOGY & Development

10th Anniversary DRUG DISCOVERY TECHNOLOGY & Development

Target-Related Affinity Profiling: Teliks Lead Discovery Technology

Target-Related Affinity Profiling (TRAP) is a computational drug discovery technology that is based on 'affinity fingerprints', which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular descriptors derived from chemical structures and shown to be a useful alternative for lead discovery. The TRAP screening process is described and two example applications are presented: I. the discovery of novel inhibitors of human intestinal carboxylesterase, and II. the discovery of novel inhibitors of cyclooxygenase-1 through the use of the affinity fingerprints of known cyclooxygenase-1 inhibitors. A summary of the complementary advantages of TRAP screening technology compared to traditional approaches to drug lead discovery concludes the review.

RNA Silencing Technologies in Drug Discovery and Target Validation

With the completion of the Human Genome Project, there is an increasing, substantial need to apply RNA silencing technologies to post-genome research. In this review, we focus on three silencing technologies: antisense, RNA interference, and ribozymes. These RNA silencing approaches are designed to specifically block gene expression, and have applications in investigations of gene function, pharmacogenetics and pharmacogenomics, and identification of novel targets for therapy. With high specificity and affinity, oligonucleotide therapeutic agents are being developed as novel treatments for various diseases such as cancer, cardiovascular diseases and infectious diseases. These drugs can be used alone or in combination with current treatment strategies including chemotherapy or radiation therapy. However, the potential of these therapeutic agents based on RNA silencing technologies has not yet been fully realized, and further investigations are needed to define their specificity and efficacy, especially in the clinical setting. Keywords: genetic therapy, rna silencing, pharmacogenetics, single nucleotide polymorphisms

Biological complexity and drug discovery: a practical systems biology approach

Drugs fail in clinical studies most often from lack of efficacy or unexpected toxicities. These failures result from an inadequate understanding of drug action and follow, in part, from our dependence on drug discovery technologies that do not take into account the complexity of human disease biology. Biological systems exhibit many features of complex engineering systems, including modularity, redundancy, robustness, and emergent properties. Addressing these features has contributed to the successful design of an improved biological assay technology for inflammation drug discovery. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), involves the statistical analysis of protein datasets generated from novel complex primary human cell-based assay systems. Compound profiling in these systems has revealed that a surprisingly large number of biological mechanisms can be detected and distinguished. Features of these assays relevant to the behaviour of complex systems are described.

Prediction of Drug Metabolism: The Case of Cytochrome P450 2D6

Cytochromes P450 (Cyt P450s) constitute the most important biotransformation enzymes involved in the biotransformation of drugs and other xenobiotics. Because drug metabolism by Cyt P450s plays such an important role in the disposition and in the pharmacological and toxicological effects of drugs, early consideration of ADME-properties is increasingly seen as essential for the discovery and the development of new drugs and drug candidates. The primary aim of this paper is to present various computational approaches used to rationalize and predict the activity and substrate selectivity of Cyt P450s, as well as the possibilities and limitations of these approaches, now and in the future. Attention is also paid to the experimental validation of these approaches by using high-throughput screening (HTS) of affinities to drug-drug interactions at the level of Cyt P450-isoenzymes. Since human Cyt P450 2D6 is one of the most important drug metabolizing enzymes and since in this regard much pioneering work has been done with this Cyt P450, Cyt P450 2D6 is chosen as a model for this discussion. Apart from early mechanism-based ab initio calculations on substrates of Cyt P450 2D6, pharmacophore modeling of ligands (i.e. both substrates and inhibitors) of Cyt P450 2D6 and protein homology modeling have been used successfully for the rationalisation and prediction of metabolite formation by this Cyt P450 isoenzyme. Significant protein structure-related species differences have been reported recently. It is concluded that not one computational approach is capable of rationalizing and reliably predicting metabolite formation by Cyt P450 2D6, but that it is rather the combination of the various complimentary approaches. It is moreover concluded, that experimental validation of the computational models and predictions is often still lacking. With the advent of novel, easily and well applicable in vitro based high throughput assays for ligand binding and turnover this limitation could be overcome soon, however. When effective links with other new and recent developments, such as bioinformatics, neural network computing, genomics and proteomics can be created, in silico rationalisation and prediction of drug metabolism by Cyt P450s is likely to become one of the key technologies in early drug discovery and development processes.

Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods

Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug-target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.

Outrunning the Bear

AbstractFor Abstract see ChemInform Abstract in Full Text.

Drug Discovery Technologies

Current Protocols in PharmacologyVolume 27, Issue 1 p. 9.0.1-9.0.2 Introduction Drug Discovery Technologies Mike Williams, Mike WilliamsSearch for more papers by this author Mike Williams, Mike WilliamsSearch for more papers by this author First published: 15 January 2005 https://doi.org/10.1002/0471141755.ph0900s27Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. View the latest in Pharmacology RelatedInformation

Development of Novel DDS Technologies for Pharmacoproteomic-based Drug Discovery and Development

With the success of the Human Genome Project, the focus of life science research has shifted to the functional and structural analyses of proteins, such as proteomics and structural genomics. These novel approaches to the analysis of proteins, including newly identified ones, are expected to help in the identification and development of protein therapies for various diseases. Thus pharmacoproteomic-based drug discovery currently has a very high profile. Nevertheless, the use of bioactive proteins in the clinical setting is not straightforward because in vivo these proteins have low stability and pleiotropic action. To promote pharmacoproteomic-based drug discovery and development, we have attempted to establish a system for creating functional mutant proteins (muteins) with the desired properties and to develop a site-specific bioconjugation system for further improving their therapeutic potency. These innovative protein-drug systems are discussed in this review.