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Drug Discovery (drug + discovery)
Kinds of Drug Discovery Terms modified by Drug Discovery Selected AbstractsTowards a New Logic for Front End Management: From Drug Discovery to Drug Design in Pharmaceutical R&DCREATIVITY AND INNOVATION MANAGEMENT, Issue 2 2007Maria Elmquist Under pressure to innovate and be cost-effective at the same time, R&D departments are being challenged to develop new organizations and processes for Front End activities. This is especially true in the pharmaceutical industry. As drug development becomes more risky and costly, the discovery departments of pharmaceutical companies are increasingly being compelled to provide strong drug candidates for efficient development processes and quick market launches. It is argued that the Fuzzy Front End consists less of the discovery or recognition of opportunities than of the building of expanded concepts: the notion of concept generation is revisited, suggesting the need for a new logic for organizing Front End activities in order to support sustainable innovative product development. Based on an in-depth empirical study at a European pharmaceutical company, this paper contributes to improved understanding of the actual management practices used in the Front End. Using a design reasoning model (the C-K model), it also adds to the growing body of literature on the management of Front End activities in new product development processes. [source] Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate-induced EpilepsyEPILEPSIA, Issue 1 2005Heidi L. Grabenstatter Summary:,Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol. Methods: Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague,Dawley rat experienced convulsive status epilepticus for >3 h. Six 1-month trials (n = 6,10 rats) assessed the effects of 0.3,100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures. Results: A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3,100 mg/kg) were dose dependent. Conclusions: These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose,effect and time-course-of-recovery studies. [source] Book Review: Applying Genomic and Proteomic Microarray Technology in Drug Discovery.PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 14 2005By Robert S. Matson No abstracts. [source] In vivo Pharmacology in Drug Discovery and DevelopmentBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2006Ove Svendsen No abstract is available for this article. [source] Rezension: Drug Discovery, a History von Walter SneaderBERICHTE ZUR WISSENSCHAFTSGESCHICHTE, Issue 2 2006Ute Mauch No abstract is available for this article. [source] Screening: Methods for Experimentation in Industry, Drug Discovery, and Genetics Edited by Dean, A. and Lewis, S.BIOMETRICS, Issue 4 2006Article first published online: 6 DEC 200 No abstract is available for this article. [source] Chemogenomics in Drug Discovery,A Medicinal Chemistry Perspective.CHEMBIOCHEM, Issue 4 2005Edited by Hugo Kubinyi, Gerhard Müller. No abstract is available for this article. [source] Transformational Leadership in Drug Discovery by Way of Virtuous Thought, Word and DeedCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Tomi K. Sawyer No abstract is available for this article. [source] Inimitable Elements of Innovative Drug Discovery: Quest for Knowledge, Passion for LifeCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2006Tomi K. Sawyer Editor-in-Chief No abstract is available for this article. [source] Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New ConceptCHEMISTRY & BIODIVERSITY, Issue 11 2009Andreas Reichel Abstract Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood,brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic. [source] The Biochemistry of Drug Metabolism , An IntroductionCHEMISTRY & BIODIVERSITY, Issue 10 2006Abstract This paper reviews the general principles and concepts underlying Drug and Xenobiotic Metabolism. Its five Chapters deal with: 1.1. Drugs and Xenobiotics, 1.2. What are Drug Disposition and Metabolism?, 1.3. Where does Drug Metabolism Occur?, 1.4. Consequences of Drug Metabolism -- An Overview, and 1.5. Drug Metabolism and Drug Discovery. This review is the first of seven Parts which will be published at intervals. The subsequent Parts will cover: 2. Redox Reactions and Their Enzymes, 3. Reactions of Hydrolysis and Their Enzymes, 4. Conjugation Reactions and Their Enzymes, 5. Metabolism and Bioactivity, 6. Inter-Individual Factors Affecting Drug Metabolism, and 7. Intra-Individual Factors Affecting Drug Metabolism. [source] Dynamic Combinatorial Chemistry in Drug Discovery, Bioorganic Chemistry, and Material Science.CHEMMEDCHEM, Issue 6 2010Edited by Benjamin Wiley, Hoboken 2010. X+265,pp., hardcover $,79.95.,ISBN,978-0-470-09603-1 [source] Epigenetic Targets in Drug Discovery.CHEMMEDCHEM, Issue 2 2010Edited by Wolfgang Sippl, Manfred Jung. Wiley-VCH, Weinheim 2009. XVI+298,pp., hardcover ,,129.00.,ISBN,978-3-527-32355-5 [source] Genomics in Drug Discovery and Development.CHEMMEDCHEM, Issue 12 2009By Dimitri Semizarov, Eric Blomme. Wiley, Hoboken 2008. 480,pp., hardcover $,115.00.,ISBN,978-0-470-09604-8 [source] How to Achieve Confidence in Drug Discovery and Development: Managing Risk (from a Reductionist to a Holistic Approach)CHEMMEDCHEM, Issue 6 2009Annette Bakker Dr. Abstract Confidence in mechanism: Creating a more holistic understanding of disease pathophysiology and an early confidence in the mechanism under investigation could help facilitate the selection of not only the most appropriate targets but also the best mechanisms for disease intervention and how to select and optimise the best compounds. Drug target and candidate selection are two of the key decision points within the drug discovery process for which all companies use certain selection criteria to make decisions on which targets to accept into their discovery pipelines and which compounds will pass into development. These steps not only help define the overall productivity of every company but they are also decisions taken without full predictive knowledge of the risks that lie ahead or how best to manage them. In particular, the process of selecting new targets does not normally involve full evaluation of the risk(s) in the mechanism under investigation (the modulation of the target), which may result in an inability to fully connect in,vitro and animal model results to the disease (clinical) setting. The resulting poor progression statistics of many compounds in the clinic is at least partially the result of a lack of understanding of disease pathophysiology. Notably, the lack of efficacy is still a major reason for failure in the clinic.1 Creating a more holistic understanding of disease pathophysiology and an early confidence in the mechanism under investigation could help facilitate the selection of not only the most appropriate targets but also the best mechanisms for disease intervention and how to select and optimise the best compounds. [source] Tissue Proteomics: Pathways, Biomarkers and Drug Discovery.CHEMMEDCHEM, Issue 5 2009C.-S., Edited by Brian Humana Press, Totowa 2008. x+225,pp., hardcover $,99.50.,ISBN,978-1-58829-679-5 [source] Computational and Structural Approaches to Drug Discovery: Ligand,Protein Interactions.CHEMMEDCHEM, Issue 7 2008Edited by Robert M. Stroud, Janet Finer-Moore. No abstract is available for this article. [source] Functional Informatics in Drug Discovery.CHEMMEDCHEM, Issue 3 2008Edited by Sergey Ilyin. No abstract is available for this article. [source] Two-dimensional protein separation in microfluidic devicesELECTROPHORESIS, Issue 5 2009Hong Chen Abstract Proteomics is emerging as an important tool in modern drug discoveries and medical diagnostics. One of the techniques used in proteomics studies is 2-DE. The process of the conventional 2-DE is time-consuming and it has substandard reproducibility. Many efforts have been made to address the limitations, with an aim for fast separation and high resolution. In this paper, we reviewed the work on achieving 2-DE in microfluidic devices, including individual dimension in one channel, two dimensions in two intersected channels, and 2-D separation in a large number of channels. We also discussed the need for integrating microvalves within 2-DE devices to prevent different separation media from contaminating with each other. Although more efforts are required to match the performance of conventional 2-DE in a slab gel, microfluidics-based 2-D separation has a potential to become an alternative in the future. [source] A novel approach and protocol for discovering extremely low-abundance proteins in serumPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 17 2006Yoshinori Tanaka Abstract The proteomic analysis of serum (plasma) has been a major approach to determining biomarkers essential for early disease diagnoses and drug discoveries. The determination of these biomarkers, however, is analytically challenging since the dynamic concentration range of serum proteins/peptides is extremely wide (more than 10,orders of magnitude). Thus, the reduction in sample complexity prior to proteomic analyses is essential, particularly in analyzing low-abundance protein biomarkers. Here, we demonstrate a novel approach to the proteomic analyses of human serum that uses an originally developed serum protein separation device and a sequentially linked 3-D-LC-MS/MS system. Our hollow-fiber-membrane-based serum pretreatment device can efficiently deplete high-molecular weight proteins and concentrate low-molecular weight proteins/peptides automatically within 1,h. Four independent analyses of healthy human sera pretreated using this unique device, followed by the 3-D-LC-MS/MS successfully produced 12,000,13,000 MS/MS spectra and hit around 1800,proteins (>95% reliability) and 2300,proteins (>80% reliability). We believe that the unique serum pretreatment device and proteomic analysis protocol reported here could be a powerful tool for searching physiological biomarkers by its high throughput (3.7,days per one sample analysis) and high performance of finding low abundant proteins from serum or plasma samples. [source] Recent Progress in Biomolecular EngineeringBIOTECHNOLOGY PROGRESS, Issue 1 2000Dewey D. Y. Ryu During the next decade or so, there will be significant and impressive advances in biomolecular engineering, especially in our understanding of the biological roles of various biomolecules inside the cell. The advances in high throughput screening technology for discovery of target molecules and the accumulation of functional genomics and proteomics data at accelerating rates will enable us to design and discover novel biomolecules and proteins on a rational basis in diverse areas of pharmaceutical, agricultural, industrial, and environmental applications. As an applied molecular evolution technology, DNA shuffling will play a key role in biomolecular engineering. In contrast to the point mutation techniques, DNA shuffling exchanges large functional domains of sequences to search for the best candidate molecule, thus mimicking and accelerating the process of sexual recombination in the evolution of life. The phage-display system of combinatorial peptide libraries will be extensively exploited to design and create many novel proteins, as a result of the relative ease of screening and identifying desirable proteins. Even though this system has so far been employed mainly in screening the combinatorial antibody libraries, its application will be extended further into the science of protein-receptor or protein-ligand interactions. The bioinformatics for genome and proteome analyses will contribute substantially toward ever more accelerated advances in the pharmaceutical industry. Biomolecular engineering will no doubt become one of the most important scientific disciplines, because it will enable systematic and comprehensive analyses of gene expression patterns in both normal and diseased cells, as well as the discovery of many new high-value molecules. When the functional genomics database, EST and SAGE techniques, microarray technique, and proteome analysis by 2-dimensional gel electrophoresis or capillary electrophoresis in combination with mass spectrometer are all put to good use, biomolecular engineering research will yield new drug discoveries, improved therapies, and significantly improved or new bioprocess technology. With the advances in biomolecular engineering, the rate of finding new high-value peptides or proteins, including antibodies, vaccines, enzymes, and therapeutic peptides, will continue to accelerate. The targets for the rational design of biomolecules will be broad, diverse, and complex, but many application goals can be achieved through the expansion of knowledge based on biomolecules and their roles and functions in cells and tissues. Some engineered biomolecules, including humanized Mab's, have already entered the clinical trials for therapeutic uses. Early results of the trials and their efficacy are positive and encouraging. Among them, Herceptin, a humanized Mab for breast cancer treatment, became the first drug designed by a biomolecular engineering approach and was approved by the FDA. Soon, new therapeutic drugs and high-value biomolecules will be designed and produced by biomolecular engineering for the treatment or prevention of not-so-easily cured diseases such as cancers, genetic diseases, age-related diseases, and other metabolic diseases. Many more industrial enzymes, which will be engineered to confer desirable properties for the process improvement and manufacturing of high-value biomolecular products at a lower production cost, are also anticipated. New metabolites, including novel antibiotics that are active against resistant strains, will also be produced soon by recombinant organisms having de novo engineered biosynthetic pathway enzyme systems. The biomolecular engineering era is here, and many of benefits will be derived from this field of scientific research for years to come if we are willing to put it to good use. [source] Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, FranceCONTRAST MEDIA & MOLECULAR IMAGING, Issue 1 2006Michael F. Tweedle Abstract This review discusses multivalency in the context of drug discovery, specifically the discovery of new diagnostic imaging and related agents. The aim is to draw attention to the powerful role that multivalency plays throughout research involving molecular biology, in general, and much of biochemically targeted contrast agent research, in particular. Two examples from the author's laboratory are described. We created small (,5,kDa) peptide ,dimers' composed of two different, chemically linked peptides. The monomer peptides both bound to the same target protein with Kd,,,100,s,nM, while the heterodimers had sub-nM Kd values. Biological activity was evident in the heterodimers where none or very little existed in homodimers, monomers or monomer mixtures. Two different tyrosine kinases (KDR and C-Met) and four peptide families produced consistent results: multivalent heterodimers were uniquely different. The second example begins with making two micron ultrasound bubbles coated with the peptide, TKPPR (a Tuftsin antagonist) as a negative control for bubbles targeted with angiogenesis target-binding peptides. Unexpected binding of a ,negative' control, (TKPPR)-targeted bubble to endothelial cells expressing angiogenesis targets, led to the surprising result that TKPPR, only when multimerized, binds avidly, specifically and actively to neuropilin-1, a VEGF co-receptor. VEGF is the primary stimulator of angiogenesis. Tuftsin is a small peptide (TKPR) derived from IgG that binds to macrophages during inflammation, and has been studied for over 30 years. The receptor has never been cloned. The results led to new conclusions about Tuftsin, neuropilin-1 and the purpose, up to now unknown, of exon 8 in VEGF. Multivalency can be used rationally to solve practical problems in drug discovery. When targeting larger structures, multivalency is frequently unavoidable, and can lead to unpredictable and useful biochemical information, as well as to new drug candidates. Copyright © 2006 John Wiley & Sons, Ltd. [source] Automated image-based phenotypic analysis in zebrafish embryosDEVELOPMENTAL DYNAMICS, Issue 3 2009Andreas Vogt Abstract Presently, the zebrafish is the only vertebrate model compatible with contemporary paradigms of drug discovery. Zebrafish embryos are amenable to automation necessary for high-throughput chemical screens, and optical transparency makes them potentially suited for image-based screening. However, the lack of tools for automated analysis of complex images presents an obstacle to using the zebrafish as a high-throughput screening model. We have developed an automated system for imaging and analyzing zebrafish embryos in multi-well plates regardless of embryo orientation and without user intervention. Images of fluorescent embryos were acquired on a high-content reader and analyzed using an artificial intelligence-based image analysis method termed Cognition Network Technology (CNT). CNT reliably detected transgenic fluorescent embryos (Tg(fli1:EGFP)y1) arrayed in 96-well plates and quantified intersegmental blood vessel development in embryos treated with small molecule inhibitors of anigiogenesis. The results demonstrate it is feasible to adapt image-based high-content screening methodology to measure complex whole organism phenotypes. Developmental Dynamics 238:656,663, 2009. © 2009 Wiley-Liss, Inc. [source] New developments in small molecules targeting p53 pathways in anticancer therapyDRUG DEVELOPMENT RESEARCH, Issue 6 2008Chit Fang Cheok Abstract The tumor suppressor p53 is frequently inactivated in a wide variety of cancers and point mutations or deletions of the p53 gene are associated with poor prognosis in cancer. About half of all human tumors carry wildtype p53 but p53 wildtype functions are often suppressed by the overexpression of murine double minute 2 (MDM2), a negative regulator of p53. Restoration of p53 functions in tumor cells, therefore, represents an attractive strategy in combating cancer and has been the focus of intensive anticancer drug discovery. One strategy is to antagonize MDM2 functions and initial success was demonstrated in vitro and in xenograft tumor models using newly discovered small molecule inhibitors and antisense oligonucleotides. The new discovery of a compound targeting SirT1 (a member of the sirtuin family) in a p53-dependent reporter screen highlighted the importance of another negative regulator of p53 and offers an additional avenue for drug discovery and research on p53-activating therapeutics. Here, we discuss the developments of p53-activating small molecules and their potential use in combination therapy with established chemotherapeutics. These small molecules were discovered from chemical library screening using biochemical assays or cellular-based assays, and/or structure-based rational drug design strategies. Drug Dev Res 69:289,296, 2008. © 2008 Wiley-Liss, Inc. [source] Monogenic migraine syndromes highlight novel drug targetsDRUG DEVELOPMENT RESEARCH, Issue 7 2007J. Jay Gargus Abstract In the post-genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering ,2 Na,K-ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co-expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy,meaning meta-stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway,genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432,440, 2007. © 2008 Wiley-Liss, Inc. [source] Nanotube Membrane Based BiosensorsELECTROANALYSIS, Issue 1-2 2004Punit Kohli Abstract We review highly sensitive detection based on electrochemical methods. These methods are based on monodisperse gold and alumina nanotubule membranes with inside diameter approaching molecular dimensions. The analyte species can be detected by measuring a change in trans-membrane current when the analyte is added to the nanotubule-based cell. The second method entails the use of a concentration change based on the nanotubule membrane. Biomemtic ion-gated channels micropore and nanotubule membrane sensors are also reviewed. These synthetic ion channels can be switched from an "off" state to an "on" state in response to an external chemical stimulus. Using these methods, we have achieved detection limits as low as 10,pM. Potential applications for these biosensors are in fields such as bioanalytical, biomedical, pharmaceutical and drug discovery. [source] Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical moleculesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2004Ronald D. Snyder Abstract Computational models are currently being used by regulatory agencies and within the pharmaceutical industry to predict the mutagenic potential of new chemical entities. These models rely heavily, although not exclusively, on bacterial mutagenicity data of nonpharmaceutical-type molecules as the primary knowledge base. To what extent, if any, this has limited the ability of these programs to predict genotoxicity of pharmaceuticals is not clear. In order to address this question, a panel of 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings was extracted from the 2000,2002 Physicians' Desk Reference and evaluated using MCASE, TOPKAT, and DEREK, the three most commonly used computational databases. These evaluations indicate a generally poor sensitivity of all systems for predicting Ames positivity (43.4,51.9% sensitivity) and even poorer sensitivity in prediction of other genotoxicities (e.g., in vitro cytogenetics positive; 21.3,31.9%). As might be expected, all three programs were more highly predictive for molecules containing carcinogenicity structural alerts (i.e., the so-called Ashby alerts; 61% ± 14% sensitivity) than for those without such alerts (12% ± 6% sensitivity). Taking all genotoxicity assay findings into consideration, there were 84 instances in which positive genotoxicity results could not be explained in terms of structural alerts, suggesting the possibility of alternative mechanisms of genotoxicity not relating to covalent drug-DNA interaction. These observations suggest that the current computational systems when applied in a traditional global sense do not provide sufficient predictivity of bacterial mutagenicity (and are even less accurate at predicting genotoxicity in tests other than the Salmonella reversion assay) to be of significant value in routine drug safety applications. This relative inability of all three programs to predict the genotoxicity of drugs not carrying obvious DNA-reactive moieties is discussed with respect to the nature of the drugs whose positive responses were not predicted and to expectations of improving the predictivity of these programs. Limitations are primarily a consequence of incomplete understanding of the fundamental genotoxic mechanisms of nonstructurally alerting drugs rather than inherent deficiencies in the computational programs. Irrespective of their predictive power, however, these programs are valuable repositories of structure-activity relationship mutagenicity data that can be useful in directing chemical synthesis in early drug discovery. Environ. Mol. Mutagen. 43:143,158, 2004. © 2004 Wiley-Liss, Inc. [source] A strategy to reduce the numbers of fish used in acute ecotoxicity testing of pharmaceuticalsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2003Thomas H. Hutchinson Abstract The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using ,42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence offish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number offish used from 3,822 to 1,025 (,73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates. [source] Quantitative structure-activity relationship methods: Perspectives on drug discovery and toxicologyENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2003Roger Perkins Abstract Quantitative structure,activity relationships (QSARs) attempt to correlate chemical structure with activity using statistical approaches. The QSAR models are useful for various purposes including the prediction of activities of untested chemicals. Quantitative structure,activity relationships and other related approaches have attracted broad scientific interest, particularly in the pharmaceutical industry for drug discovery and in toxicology and environmental science for risk assessment. An assortment of new QSAR methods have been developed during the past decade, most of them focused on drug discovery. Besides advancing our fundamental knowledge of QSARs, these scientific efforts have stimulated their application in a wider range of disciplines, such as toxicology, where QSARs have not yet gained full appreciation. In this review, we attempt to summarize the status of QSAR with emphasis on illuminating the utility and limitations of QSAR technology. We will first review two-dimensional (2D) QSAR with a discussion of the availability and appropriate selection of molecular descriptors. We will then proceed to describe three-dimensional (3D) QSAR and key issues associated with this technology, then compare the relative suitability of 2D and 3D QSAR for different applications. Given the recent technological advances in biological research for rapid identification of drug targets, we mention several examples in which QSAR approaches are employed in conjunction with improved knowledge of the structure and function of the target receptor. The review will conclude by discussing statistical validation of QSAR models, a topic that has received sparse attention in recent years despite its critical importance. [source] Human telomeric G-quadruplex: The current status of telomeric G-quadruplexes as therapeutic targets in human cancerFEBS JOURNAL, Issue 5 2010Stephen Neidle The 3,-ends of human chromosomal DNA terminate in short single-stranded guanine-rich tandem-repeat sequences. In cancer cells, these are associated with the telomere-maintenance enzyme telomerase together with the end-binding protein hPOT1. Small molecules that can compete with these proteins and induce the single-stranded DNA to form quadruplex,ligand complexes are, in effect, able to expose these 3,-ends, which results in the activation of a DNA damage response and selective inhibition of cell growth. Several of these G-quadruplex binding molecules have shown promising anticancer activity in tumour xenograft models, which indicate that the approach may be applicable to the treatment of a wide range of human cancers. This minireview summarizes the available data on these compounds and the challenges posed for drug discovery. [source] | ||||||||||||||||||||||||||||||||||||||||