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Sample records for drug discovery perspective

  1. Perspectives on bioanalytical mass spectrometry and automation in drug discovery.

    PubMed

    Janiszewski, John S; Liston, Theodore E; Cole, Mark J

    2008-11-01

    The use of high speed synthesis technologies has resulted in a steady increase in the number of new chemical entities active in the drug discovery research stream. Large organizations can have thousands of chemical entities in various stages of testing and evaluation across numerous projects on a weekly basis. Qualitative and quantitative measurements made using LC/MS are integrated throughout this process from early stage lead generation through candidate nomination. Nearly all analytical processes and procedures in modern research organizations are automated to some degree. This includes both hardware and software automation. In this review we discuss bioanalytical mass spectrometry and automation as components of the analytical chemistry infrastructure in pharma. Analytical chemists are presented as members of distinct groups with similar skillsets that build automated systems, manage test compounds, assays and reagents, and deliver data to project teams. The ADME-screening process in drug discovery is used as a model to highlight the relationships between analytical tasks in drug discovery. Emerging software and process automation tools are described that can potentially address gaps and link analytical chemistry related tasks. The role of analytical chemists and groups in modern 'industrialized' drug discovery is also discussed. PMID:18991596

  2. CACO-2 CELL LINES IN DRUG DISCOVERY- AN UPDATED PERSPECTIVE

    PubMed Central

    Kumar, Kalyan K.V; Karnati, Swathi; Reddy, Mamatha B; Chandramouli, R

    2010-01-01

    Cell lines are the invitro models used for the drug permeability studies in the preclinical and clinical phases of the drug discovery. Cell line models are simple and quick to use and avoids the usage of animal models for pharmacological and toxicological studies and hence cost effective, produce reliable and reproducible results for understanding and evaluating the permeability characteristics of the potential lead drug candidates. Different cell line models used in the drug permeability studies, their characteristics has been summarized emphasizing on CACO-2. By virtue of its merits, CACO-2 cell line development, transport experiments, automated assays, optimization of experimental conditions and mechanistic uses of CACO-2 cell lines dealt comprehensively in the following context. PMID:24825967

  3. Perspectives on NMR in drug discovery: a technique comes of age

    PubMed Central

    Pellecchia, Maurizio; Bertini, Ivano; Cowburn, David; Dalvit, Claudio; Giralt, Ernest; Jahnke, Wolfgang; James, Thomas L.; Homans, Steve W.; Kessler, Horst; Luchinat, Claudio; Meyer, Bernd; Oschkinat, Hartmut; Peng, Jeff; Schwalbe, Harald; Siegal, Gregg

    2009-01-01

    In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility. PMID:19172689

  4. Homology Modeling a Fast Tool for Drug Discovery: Current Perspectives

    PubMed Central

    Vyas, V. K.; Ukawala, R. D.; Ghate, M.; Chintha, C.

    2012-01-01

    Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery. PMID:23204616

  5. Malaria in South America: a drug discovery perspective

    PubMed Central

    2013-01-01

    The challenge of controlling and eventually eradicating malaria means that new tools are urgently needed. South America’s role in this fight spans both ends of the research and development spectrum: both as a continent capable of discovering and developing new medicines, and also as a continent with significant numbers of malaria patients. This article reviews the contribution of groups in the South American continent to the research and development of new medicines over the last decade. Therefore, the current situation of research targeting malaria control and eradication is discussed, including endemicity, geographical distribution, treatment, drug-resistance and diagnosis. This sets the scene for a review of efforts within South America to discover and optimize compounds with anti-malarial activity. PMID:23706107

  6. Virtual screening in drug discovery -- a computational perspective.

    PubMed

    Reddy, A Srinivas; Pati, S Priyadarshini; Kumar, P Praveen; Pradeep, H N; Sastry, G Narahari

    2007-08-01

    Virtual screening emerged as an important tool in our quest to access novel drug like compounds. There are a wide range of comparable and contrasting methodological protocols available in screening databases for the lead compounds. The number of methods and software packages which employ the target and ligand based virtual screening are increasing at a rapid pace. However, the general understanding on the applicability and limitations of these methodologies is not emerging as fast as the developments of various methods. Therefore, it is extremely important to compare and contrast various protocols with practical examples to gauge the strength and applicability of various methods. The review provides a comprehensive appraisal on several of the available virtual screening methods to-date. Recent developments of the docking and similarity based methods have been discussed besides the descriptor selection and pharmacophore based searching. The review touches upon the application of statistical, graph theory based methods machine learning tools in virtual screening and combinatorial library design. Finally, several case studies are undertaken where the virtual screening technology has been applied successfully. A critical analysis of these case studies provides a good platform to estimate the applicability of various virtual screening methods in the new lead identification and optimization. PMID:17696867

  7. ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

    PubMed Central

    Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

    2009-01-01

    The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

  8. Role of transport proteins in drug discovery and development: a pharmaceutical perspective.

    PubMed

    Ayrton, A; Morgan, P

    2008-07-01

    1. This review will explore, from a pharmaceutical industry perspective, the evidence and consequences of transport protein involvement in pharmacokinetic variability and safety of drugs in humans. With the preclinical and clinical evidence available, the transport proteins that are considered to be the most important in respect of pharmacokinetic variability and safety in humans will be highlighted. 2. A large number of transport proteins have been identified, at both the genetic and the cellular level, which have been suggested to play some role in the absorption, distribution or elimination of endogenous, xenobiotic or drug substrates. 3. The weight of evidence suggests that only a small number of transport proteins need to be routinely considered in the drug-discovery setting driven by the magnitude of their impact on tissue distribution, pharmacokinetic variability and drug-drug interactions. 4. For the majority of candidate drugs, an assessment of the role of transporter proteins in their disposition and safety need only be assessed if in vivo properties suggest that active transport is likely to be a significant factor, if transport proteins are implicated in a particular therapeutic target area or if the disposition and safety of a likely co-medication are known to be significantly modulated by transport proteins. PMID:18668427

  9. Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

    PubMed Central

    Andreol, Federico; Barbosa, Arménio Jorge Moura; Daniele Parenti, Marco; Rio, Alberto Del

    2013-01-01

    Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of small-molecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives. PMID:23016851

  10. Approaches to target identification and validation for tuberculosis drug discovery: a UCT perspective.

    PubMed

    Warner, Digby F; Mizrahi, Valerie

    2012-06-01

    Tuberculosis (TB) disproportionately affects a few high-burden countries including South Africa. In these regions, basic TB research is rare, endemic countries being valued primarily as sites for drug trials and clinical studies. Our basic mycobacterial research focuses on current approaches to drug target identification and validation within the context of international trends in TB drug discovery. Increased funding for TB drug development globally prompted a significant shift in the composition of drug discovery consortia, with academic laboratories assuming a major role in collaboration with industrial partners. This hybrid model holds promise for the expansion of local programmes, especially where actively supported by government. However, the application of industry-standard business practices to research projects involving biology and chemistry expertise demands a greater appreciation of the differences between a chemically, versus biologically, validated drug target, and of the factors informing these differences. PMID:22668936

  11. Computational drug discovery

    PubMed Central

    Ou-Yang, Si-sheng; Lu, Jun-yan; Kong, Xiang-qian; Liang, Zhong-jie; Luo, Cheng; Jiang, Hualiang

    2012-01-01

    Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field. PMID:22922346

  12. Drug discovery in academia.

    PubMed

    Verkman, A S

    2004-03-01

    Drug discovery and development is generally done in the commercial rather than the academic realm. Drug discovery involves target discovery and validation, lead identification by high-throughput screening, and lead optimization by medicinal chemistry. Follow-up preclinical evaluation includes analysis in animal models of compound efficacy and pharmacology (ADME: administration, distribution, metabolism, elimination) and studies of toxicology, specificity, and drug interactions. Notwithstanding the high-cost, labor-intensive, and non-hypothesis-driven aspects of drug discovery, the academic setting has a unique and expanding niche in this important area of investigation. For example, academic drug discovery can focus on targets of limited commercial value, such as third-world and rare diseases, and on the development of research reagents such as high-affinity inhibitors for pharmacological "gene knockout" in animal models ("chemical genetics"). This review describes the practical aspects of the preclinical drug discovery process for academic investigators. The discovery of small molecule inhibitors and activators of the cystic fibrosis transmembrane conductance regulator is presented as an example of an academic drug discovery program that has yielded new compounds for physiology research and clinical development. PMID:14761879

  13. Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective.

    PubMed

    Karawajczyk, Anna; Giordanetto, Fabrizio; Benningshof, Jorg; Hamza, Daniel; Kalliokoski, Tuomo; Pouwer, Kees; Morgentin, Remy; Nelson, Adam; Müller, Gerhard; Piechot, Alexander; Tzalis, Dimitrios

    2015-11-01

    High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes. PMID:26429298

  14. Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company

    PubMed Central

    Gromo, G.; Mann, J.; Fitzgerald, J.D.

    2014-01-01

    The theme of this review is to summarize the evolving processes in cardiovascular drug discovery and development within a large pharmaceutical company. Emphasis is placed on the contrast between the academic and industrial research operating environments, which can influence the effectiveness of research collaboration between the two constituencies, but which plays such an important role in drug innovation. The strategic challenges that research directors face are also emphasized. The need for improved therapy in many cardiovascular indications remains high, but the feasibility in making progress, despite the advances in molecular biology and genomics, is also assessed. PMID:24890831

  15. Antibiotic drug discovery.

    PubMed

    Wohlleben, Wolfgang; Mast, Yvonne; Stegmann, Evi; Ziemert, Nadine

    2016-09-01

    Due to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a 'New Age of Antibiotic Discovery'. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years. PMID:27470984

  16. Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

    PubMed

    Marugán, Carlos; Torres, Raquel; Lallena, María José

    2015-01-01

    Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors. PMID:26779442

  17. Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives

    PubMed Central

    Marugán, Carlos; Torres, Raquel; Lallena, María José

    2016-01-01

    Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors. PMID:26779442

  18. Assessment of drug metabolism enzyme and transporter pharmacogenetics in drug discovery and early development: perspectives of the I-PWG.

    PubMed

    Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing

    2016-04-01

    Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition. PMID:27045656

  19. Toxins and drug discovery.

    PubMed

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. PMID:25448391

  20. Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery

    PubMed Central

    Imbrici, Paola; Liantonio, Antonella; Camerino, Giulia M.; De Bellis, Michela; Camerino, Claudia; Mele, Antonietta; Giustino, Arcangela; Pierno, Sabata; De Luca, Annamaria; Tricarico, Domenico; Desaphy, Jean-Francois; Conte, Diana

    2016-01-01

    In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets. PMID:27242528

  1. Drug discovery in jeopardy

    PubMed Central

    Cuatrecasas, Pedro

    2006-01-01

    Despite striking advances in the biomedical sciences, the flow of new drugs has slowed to a trickle, impairing therapeutic advances as well as the commercial success of drug companies. Reduced productivity in the drug industry is caused mainly by corporate policies that discourage innovation. This is compounded by various consequences of mega-mergers, the obsession for blockbuster drugs, the shift of control of research from scientists to marketers, the need for fast sales growth, and the discontinuation of development compounds for nontechnical reasons. Lessons from the past indicate that these problems can be overcome, and herein, new and improved directions for drug discovery are suggested. PMID:17080187

  2. A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine

    PubMed Central

    Stern, Andrew M.; Schurdak, Mark E.; Bahar, Ivet; Berg, Jeremy M.; Taylor, D. Lansing

    2016-01-01

    Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)–driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. PMID:26962875

  3. A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine.

    PubMed

    Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet; Berg, Jeremy M; Taylor, D Lansing

    2016-07-01

    Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)-driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. PMID:26962875

  4. Optogenetics enlightens neuroscience drug discovery.

    PubMed

    Song, Chenchen; Knöpfel, Thomas

    2016-02-01

    Optogenetics - the use of light and genetics to manipulate and monitor the activities of defined cell populations - has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery. PMID:26612666

  5. Marine microorganism-invertebrate assemblages: perspectives to solve the "supply problem" in the initial steps of drug discovery.

    PubMed

    Leal, Miguel Costa; Sheridan, Christopher; Osinga, Ronald; Dionísio, Gisela; Rocha, Rui Jorge Miranda; Silva, Bruna; Rosa, Rui; Calado, Ricardo

    2014-07-01

    The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the "blue gold" in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts. PMID:24983638

  6. Marine Microorganism-Invertebrate Assemblages: Perspectives to Solve the “Supply Problem” in the Initial Steps of Drug Discovery

    PubMed Central

    Leal, Miguel Costa; Sheridan, Christopher; Osinga, Ronald; Dionísio, Gisela; Rocha, Rui Jorge Miranda; Silva, Bruna; Rosa, Rui; Calado, Ricardo

    2014-01-01

    The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the “blue gold” in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts. PMID:24983638

  7. Computer-aided drug discovery

    PubMed Central

    Bajorath, Jürgen

    2015-01-01

    Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience. PMID:26949519

  8. Intercellular Lipid Mediators and GPCR Drug Discovery

    PubMed Central

    Im, Dong-Soon

    2013-01-01

    G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed. PMID:24404331

  9. Deep Learning in Drug Discovery.

    PubMed

    Gawehn, Erik; Hiss, Jan A; Schneider, Gisbert

    2016-01-01

    Artificial neural networks had their first heyday in molecular informatics and drug discovery approximately two decades ago. Currently, we are witnessing renewed interest in adapting advanced neural network architectures for pharmaceutical research by borrowing from the field of "deep learning". Compared with some of the other life sciences, their application in drug discovery is still limited. Here, we provide an overview of this emerging field of molecular informatics, present the basic concepts of prominent deep learning methods and offer motivation to explore these techniques for their usefulness in computer-assisted drug discovery and design. We specifically emphasize deep neural networks, restricted Boltzmann machine networks and convolutional networks. PMID:27491648

  10. Drug discovery: lessons from evolution

    PubMed Central

    Warren, John

    2011-01-01

    A common view within the pharmaceutical industry is that there is a problem with drug discovery and we should do something about it. There is much sympathy for this from academics, regulators and politicians. In this article I propose that lessons learnt from evolution help identify those factors that favour successful drug discovery. This personal view is influenced by a decade spent reviewing drug development programmes submitted for European regulatory approval. During the prolonged gestation of a new medicine few candidate molecules survive. This process of elimination of many variants and the survival of so few has much in common with evolution, an analogy that encourages discussion of the forces that favour, and those that hinder, successful drug discovery. Imagining a world without vaccines, anaesthetics, contraception and anti-infectives reveals how medicines revolutionized humanity. How to manipulate conditions that favour such discoveries is worth consideration. PMID:21395642

  11. Systems Pharmacology in Small Molecular Drug Discovery.

    PubMed

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  12. Systems Pharmacology in Small Molecular Drug Discovery

    PubMed Central

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  13. Label-free drug discovery

    PubMed Central

    Fang, Ye

    2014-01-01

    Current drug discovery is dominated by label-dependent molecular approaches, which screen drugs in the context of a predefined and target-based hypothesis in vitro. Given that target-based discovery has not transformed the industry, phenotypic screen that identifies drugs based on a specific phenotype of cells, tissues, or animals has gained renewed interest. However, owing to the intrinsic complexity in drug–target interactions, there is often a significant gap between the phenotype screened and the ultimate molecular mechanism of action sought. This paper presents a label-free strategy for early drug discovery. This strategy combines label-free cell phenotypic profiling with computational approaches, and holds promise to bridge the gap by offering a kinetic and holistic representation of the functional consequences of drugs in disease relevant cells that is amenable to mechanistic deconvolution. PMID:24723889

  14. Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists.

    PubMed

    Jones, Alan Wayne

    2016-01-01

    Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H1 and H2 receptors are the subject of this review. Pharmaceutical products that block H1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H3 and H4 receptors and the therapeutic potential is gradually being appreciated. PMID:27119574

  15. Trends in Modern Drug Discovery.

    PubMed

    Eder, Jörg; Herrling, Paul L

    2016-01-01

    Drugs discovered by the pharmaceutical industry over the past 100 years have dramatically changed the practice of medicine and impacted on many aspects of our culture. For many years, drug discovery was a target- and mechanism-agnostic approach that was based on ethnobotanical knowledge often fueled by serendipity. With the advent of modern molecular biology methods and based on knowledge of the human genome, drug discovery has now largely changed into a hypothesis-driven target-based approach, a development which was paralleled by significant environmental changes in the pharmaceutical industry. Laboratories became increasingly computerized and automated, and geographically dispersed research sites are now more and more clustered into large centers to capture technological and biological synergies. Today, academia, the regulatory agencies, and the pharmaceutical industry all contribute to drug discovery, and, in order to translate the basic science into new medical treatments for unmet medical needs, pharmaceutical companies have to have a critical mass of excellent scientists working in many therapeutic fields, disciplines, and technologies. The imperative for the pharmaceutical industry to discover breakthrough medicines is matched by the increasing numbers of first-in-class drugs approved in recent years and reflects the impact of modern drug discovery approaches, technologies, and genomics. PMID:26330257

  16. Principles of early drug discovery

    PubMed Central

    Hughes, JP; Rees, S; Kalindjian, SB; Philpott, KL

    2011-01-01

    Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15 years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development. PMID:21091654

  17. Tools for GPCR drug discovery

    PubMed Central

    Zhang, Ru; Xie, Xin

    2012-01-01

    G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functional selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening (HTS). In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery. PMID:22266728

  18. PEDF as an anticancer drug and new treatment methods following the discovery of its receptors: A patent perspective

    PubMed Central

    Manalo, Katrina B.; Choong, Peter F.M.; Becerra, S. Patricia; Dass, Crispin R.

    2014-01-01

    Background Traditional forms of cancer therapy, which includes chemotherapy, have largely been overhauled due to the significant degree of toxicity they pose to normal, otherwise healthy tissue. It is hoped that use of biological agents, most of which are endogenously present in the body, will lead to safer treatment outcomes, without sacrificing efficacy. Objective The finding that PEDF, a naturally-occurring protein, was a potent angiogenesis inhibitor became the basis for studying the role of PEDF in tumours that are highly resistant to chemotherapy. The determination of the direct role of PEDF against cancer paved the way for understanding and developing PEDF as a novel drug. This review focuses on the patent applications behind testing the anticancer therapeutic effect of PEDF via its receptors as an antiangiogenic agent and as a direct anticancer agent. Conclusions The majority of the PEDF patents describe its and/or its fragments’ antiangiogenic ability and the usage of recombinant vectors as the mode of treatment delivery. PEDF’s therapeutic potential against different diseases and the discovery of its receptors opens possibilities for improving PEDF-based peptide design and drug delivery modes. PMID:21204726

  19. Computational Methods in Drug Discovery

    PubMed Central

    Sliwoski, Gregory; Kothiwale, Sandeepkumar; Meiler, Jens

    2014-01-01

    Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature. PMID:24381236

  20. Serendipity in anticancer drug discovery.

    PubMed

    Hargrave-Thomas, Emily; Yu, Bo; Reynisson, Jóhannes

    2012-01-10

    It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered following an incident in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind. PMID:22247822

  1. Serendipity in anticancer drug discovery

    PubMed Central

    Hargrave-Thomas, Emily; Yu, Bo; Reynisson, Jóhannes

    2012-01-01

    It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered following an incident in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind. PMID:22247822

  2. Drug discovery in ovarian cancer.

    PubMed

    Chase, Dana M; Mathur, Nidhee; Tewari, Krishnansu S

    2010-11-01

    Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligand-binding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of alpha5beta1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed. PMID:20524931

  3. Mitigating risk in academic preclinical drug discovery.

    PubMed

    Dahlin, Jayme L; Inglese, James; Walters, Michael A

    2015-04-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

  4. Emerging drug discovery approaches for selective targeting of “precursor” metastatic breast cancer cells: highlights and perspectives

    PubMed Central

    AAlaoui-Jamali, Moulay; Bijian, Krikor; Batist, Gerald

    2011-01-01

    CSC properties. These exciting concepts have led to the formulation of various approaches for targeting precursor metastatic cells, and these have taken on greater priority in therapeutic drug discovery research by both academia and pharmaceuticals. In this review, we focus on current efforts in medicinal chemistry to develop small molecules able to target precursor metastatic cells via interference with the CSC/EMT differentiation program, self-renewal, and survival. It is not meant to be comprehensive and the reader is referred to selected reviews that provide coverage of related basic aspects. Rather, emphasis is given to promising molecules with CSC/EMT signaling at the preclinical stage and in clinical trials that are paving the way to new generations of anti-metastasis drugs. PMID:22046485

  5. The role of serendipity in drug discovery

    PubMed Central

    Ban, Thomas A.

    2006-01-01

    Serendipity is one of the many factors that may contribute to drug discovery. It has played a role in the discovery of prototype psychotropic drugs that led to modern pharmacological treatment in psychiatry. It has also played a role in the discovery of several drugs that have had an impact on the development of psychiatry, “Serendipity” in drug discovery implies the finding of one thing while looking for something else. This was the case in six of the twelve serendipitous discoveries reviewed in this paper, ie, aniline purple, penicillin, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine, in the case of three drugs, ie, potassium bromide, chloral hydrate, and lithium, the discovery was serendipitous because an utterly false rationale led to correct empirical results; and in case of two others, ie, iproniazid and sildenafil, because valuable indications were found for these drugs which were not initially those sought. The discovery of one of the twelve drugs, chlordiazepoxide, was sheer luck. PMID:17117615

  6. Drug Discovery from Marine Microbes

    PubMed Central

    Gerwick, William H.; Fenner, Amanda M.

    2013-01-01

    The marine environment has been a source of more than 20,000 inspirational natural products discovered over the past 50 years. From these efforts, 9 approved drugs and 12 current clinical trial agents have been discovered, either as natural products or molecules inspired from the natural product structure. To a significant degree, these have come from collections of marine invertebrates largely obtained from shallow water tropical ecosystems. However, there is a growing recognition that marine invertebrates are oftentimes populated with enormous quantities of ‘associated’ or symbiotic microorganisms, and that microorganisms are the true metabolic sources of these most valuable of marine natural products. Also, because of the inherently multidisciplinary nature of this field, a high degree of innovation is characteristic of marine natural product drug discovery efforts. PMID:23274881

  7. Hemozoin and antimalarial drug discovery

    PubMed Central

    Fong, Kim Y; Wright, David W

    2014-01-01

    Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 ‘highly druggable’ initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite. PMID:23919553

  8. Lysophospholipid receptors in drug discovery

    PubMed Central

    Kihara, Yasuyuki; Mizuno, Hirotaka; Chun, Jerold

    2014-01-01

    Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1–6, S1P1–5, LPI1, and LysoPS1–3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as is a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. PMID:25499971

  9. Lysophospholipid receptors in drug discovery.

    PubMed

    Kihara, Yasuyuki; Mizuno, Hirotaka; Chun, Jerold

    2015-05-01

    Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. PMID:25499971

  10. Pluripotent stem cells to model Hutchinson-Gilford progeria syndrome (HGPS): Current trends and future perspectives for drug discovery.

    PubMed

    Lo Cicero, Alessandra; Nissan, Xavier

    2015-11-01

    Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (p.G608G) of the LMNA, leading to the production of a mutated form of lamin A precursor called progerin. In HGPS, progerin accumulates in cells causing progressive molecular defects, including nuclear shape abnormalities, chromatin disorganization, damage to DNA and delays in cell proliferation. Here we report how, over the past five years, pluripotent stem cells have provided new insights into the study of HGPS and opened new original therapeutic perspectives to treat the disease. PMID:26474742

  11. TOXICOGENOMICS DRUG DISCOVERY AND THE PATHOLOGIST

    EPA Science Inventory

    Toxicogenomics, drug discovery, and pathologist.

    The field of toxicogenomics, which currently focuses on the application of large-scale differential gene expression (DGE) data to toxicology, is starting to influence drug discovery and development in the pharmaceutical indu...

  12. The future of crystallography in drug discovery

    PubMed Central

    Zheng, Heping; Hou, Jing; Zimmerman, Matthew D; Wlodawer, Alexander; Minor, Wladek

    2014-01-01

    Introduction X-ray crystallography plays an important role in structure-based drug design (SBDD), and accurate analysis of crystal structures of target macromolecules and macromolecule–ligand complexes is critical at all stages. However, whereas there has been significant progress in improving methods of structural biology, particularly in X-ray crystallography, corresponding progress in the development of computational methods (such as in silico high-throughput screening) is still on the horizon. Crystal structures can be overinterpreted and thus bias hypotheses and follow-up experiments. As in any experimental science, the models of macromolecular structures derived from X-ray diffraction data have their limitations, which need to be critically evaluated and well understood for structure-based drug discovery. Areas covered This review describes how the validity, accuracy and precision of a protein or nucleic acid structure determined by X-ray crystallography can be evaluated from three different perspectives: i) the nature of the diffraction experiment; ii) the interpretation of an electron density map; and iii) the interpretation of the structural model in terms of function and mechanism. The strategies to optimally exploit a macromolecular structure are also discussed in the context of ‘Big Data’ analysis, biochemical experimental design and structure-based drug discovery. Expert opinion Although X-ray crystallography is one of the most detailed ‘microscopes’ available today for examining macromolecular structures, the authors would like to re-emphasize that such structures are only simplified models of the target macromolecules. The authors also wish to reinforce the idea that a structure should not be thought of as a set of precise coordinates but rather as a framework for generating hypotheses to be explored. Numerous biochemical and biophysical experiments, including new diffraction experiments, can and should be performed to verify or falsify

  13. Open PHACTS: semantic interoperability for drug discovery.

    PubMed

    Williams, Antony J; Harland, Lee; Groth, Paul; Pettifer, Stephen; Chichester, Christine; Willighagen, Egon L; Evelo, Chris T; Blomberg, Niklas; Ecker, Gerhard; Goble, Carole; Mons, Barend

    2012-11-01

    Open PHACTS is a public-private partnership between academia, publishers, small and medium sized enterprises and pharmaceutical companies. The goal of the project is to deliver and sustain an 'open pharmacological space' using and enhancing state-of-the-art semantic web standards and technologies. It is focused on practical and robust applications to solve specific questions in drug discovery research. OPS is intended to facilitate improvements in drug discovery in academia and industry and to support open innovation and in-house non-public drug discovery research. This paper lays out the challenges and how the Open PHACTS project is hoping to address these challenges technically and socially. PMID:22683805

  14. Scaffold Repurposing of Old Drugs Towards New Cancer Drug Discovery.

    PubMed

    Chen, Haijun; Wu, Jianlei; Gao, Yu; Chen, Haiying; Zhou, Jia

    2016-01-01

    As commented by the Nobelist James Black that "The most fruitful basis of the discovery of a new drug is to start with an old drug", drug repurposing represents an attractive drug discovery strategy. Despite the success of several repurposed drugs on the market, the ultimate therapeutic potential of a large number of non-cancer drugs is hindered during their repositioning due to various issues including the limited efficacy and intellectual property. With the increasing knowledge about the pharmacological properties and newly identified targets, the scaffolds of the old drugs emerge as a great treasure-trove towards new cancer drug discovery. In this review, we summarize the recent advances in the development of novel small molecules for cancer therapy by scaffold repurposing with highlighted examples. The relevant strategies, advantages, challenges and future research directions associated with this approach are also discussed. PMID:26881709

  15. Introduction to fragment-based drug discovery.

    PubMed

    Erlanson, Daniel A

    2012-01-01

    Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement. PMID:21695633

  16. Antifungal drug discovery: the process and outcomes

    PubMed Central

    Calderone, Richard; Sun, Nuo; Gay-Andrieu, Francoise; Groutas, William; Weerawarna, Pathum; Prasad, Sridhar; Alex, Deepu; Li, Dongmei

    2014-01-01

    New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery. PMID:25046525

  17. A unified approach to computational drug discovery.

    PubMed

    Tseng, Chih-Yuan; Tuszynski, Jack

    2015-11-01

    It has been reported that a slowdown in the development of new medical therapies is affecting clinical outcomes. The FDA has thus initiated the Critical Path Initiative project investigating better approaches. We review the current strategies in drug discovery and focus on the advantages of the maximum entropy method being introduced in this area. The maximum entropy principle is derived from statistical thermodynamics and has been demonstrated to be an inductive inference tool. We propose a unified method to drug discovery that hinges on robust information processing using entropic inductive inference. Increasingly, applications of maximum entropy in drug discovery employ this unified approach and demonstrate the usefulness of the concept in the area of pharmaceutical sciences. PMID:26189935

  18. Antifungal drug discovery: the process and outcomes.

    PubMed

    Calderone, Richard; Sun, Nuo; Gay-Andrieu, Francoise; Groutas, William; Weerawarna, Pathum; Prasad, Sridhar; Alex, Deepu; Li, Dongmei

    2014-01-01

    New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that 'repurposing' compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery. PMID:25046525

  19. Role of ligand-based drug design methodologies toward the discovery of new anti- Alzheimer agents: futures perspectives in Fragment-Based Ligand Design.

    PubMed

    Speck-Planche, A; Luan, F; Cordeiro, M N D S

    2012-01-01

    Alzheimer's disease (AD), a degenerative disease affecting the brain, is the single most common source of dementia in adults. The cause and the progression of AD still remains a mystery among medical experts. As a result, a cure has not yet been discovered, even after decade's worth of research that started since 1906, when the disease was first identified. Despite the efforts of the scientific community, several of the biological receptors associated with AD have not been sufficiently studied to date, limiting in turn the design of new and more potent anti-AD agents. Thus, the search for new drug candidates as inhibitors of different targets associated with AD constitutes an essential part towards the discovery of new and more efficient anti-AD therapies. The present work is focused on the role of the Ligand-Based Drug Design (LBDD) methodologies which have been applied for the elucidation of new molecular entities with high inhibitory activity against targets related with AD. Particular emphasis is given also to the current state of fragment-based ligand approaches as alternatives of the Fragment-Based Drug Discovery (FBDD) methodologies. Finally, several guidelines are offered to show how the use of fragment-based descriptors can be determinant for the design of multi-target inhibitors of proteins associated with AD. PMID:22376033

  20. Structural genomics-impact on biomedicine and drug discovery.

    PubMed

    Weigelt, Johan

    2010-05-01

    The field of structural genomics emerged as one of many 'omics disciplines more than a decade ago, and a multitude of large scale initiatives have been launched across the world. Development and implementation of methods for high-throughput structural biology represents a common denominator among different structural genomics programs. From another perspective a distinction between "biology-driven" versus "structure-driven" approaches can be made. This review outlines the general themes of structural genomics, its achievements and its impact on biomedicine and drug discovery. The growing number of high resolution structures of known and potential drug target proteins is expected to have tremendous value for future drug discovery programs. Moreover, the availability of large numbers of purified proteins enables generation of tool reagents, such as chemical probes and antibodies, to further explore protein function in the cell. PMID:20211166

  1. Research & market strategy: how choice of drug discovery approach can affect market position.

    PubMed

    Sams-Dodd, Frank

    2007-04-01

    In principal, drug discovery approaches can be grouped into target- and function-based, with the respective aims of developing either a target-selective drug or a drug that produces a specific biological effect irrespective of its mode of action. Most analyses of drug discovery approaches focus on productivity, whereas the strategic implications of the choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the perspective of market position indicates that the functional approach is superior for the development of novel, innovative treatments. PMID:17395091

  2. Designer drugs: the evolving science of drug discovery.

    PubMed

    Wanke, L A; DuBose, R F

    1998-07-01

    Drug discovery and design are fundamental to drug development. Until recently, most drugs were discovered through random screening or developed through molecular modification. New technologies are revolutionizing this phase of drug development. Rational drug design, using powerful computers and computational chemistry and employing X-ray crystallography, nuclear magnetic resonance spectroscopy, and three-dimensional quantitative structure activity relationship analysis, is creating highly specific, biologically active molecules by virtual reality modeling. Sophisticated screening technologies are eliminating all but the most active lead compounds. These new technologies promise more efficacious, safe, and cost-effective medications, while minimizing drug development time and maximizing profits. PMID:10185235

  3. The discovery of drug-induced illness.

    PubMed

    Jick, H

    1977-03-01

    The increased use of drugs (and the concurrent increased risks of drug-induced illness) require definition of relevant research areas and strategy. For established marketed drugs, research needs depend on the magnitudes of risk of an illness from a drug and the base-line risk. With the drug risk high and the base-line risk low, the problem surfaces in premarketing studies or through the epidemic that develops after marketing. If the drug adds slightly to a high base-line risk, the effect is undetectable. When both risks are low, adverse effects can be discovered by chance, but systematic case-referent studies can speed discovery. If both risks are high, clinical trials and nonexperimental studies may be used. With both risks intermediate, systematic evaluations, especially case-referent studies are needed. Newly marketed drugs should be routinely evaluated through compulsory registration and follow-up study of the earliest users. PMID:834226

  4. Boesenbergia rotunda: From Ethnomedicine to Drug Discovery

    PubMed Central

    Eng-Chong, Tan; Yean-Kee, Lee; Chin-Fei, Chee; Choon-Han, Heh; Sher-Ming, Wong; Li-Ping, Christina Thio; Gen-Teck, Foo; Khalid, Norzulaani; Abd Rahman, Noorsaadah; Karsani, Saiful Anuar; Othman, Shatrah; Othman, Rozana; Yusof, Rohana

    2012-01-01

    Boesenbergia rotunda is a herb from the Boesenbergia genera under the Zingiberaceae family. B. rotunda is widely found in Asian countries where it is commonly used as a food ingredient and in ethnomedicinal preparations. The popularity of its ethnomedicinal usage has drawn the attention of scientists worldwide to further investigate its medicinal properties. Advancement in drug design and discovery research has led to the development of synthetic drugs from B. rotunda metabolites via bioinformatics and medicinal chemistry studies. Furthermore, with the advent of genomics, transcriptomics, proteomics, and metabolomics, new insights on the biosynthetic pathways of B. rotunda metabolites can be elucidated, enabling researchers to predict the potential bioactive compounds responsible for the medicinal properties of the plant. The vast biological activities exhibited by the compounds obtained from B. rotunda warrant further investigation through studies such as drug discovery, polypharmacology, and drug delivery using nanotechnology. PMID:23243448

  5. Arthritis Genetics Analysis Aids Drug Discovery

    MedlinePlus

    ... biological insights for drug discovery,” Plenge says. —by Carol Torgan, Ph.D. Related Links Gut Microbes Linked ... Assistant Editors: Vicki Contie, Tianna Hicklin, Ph.D., Carol Torgan, Ph.D. NIH Research Matters is a ...

  6. Open drug discovery for the Zika virus

    PubMed Central

    Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina

    2016-01-01

    The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks. PMID:27134728

  7. Open drug discovery for the Zika virus.

    PubMed

    Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina

    2016-01-01

    The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks. PMID:27134728

  8. Haemonchus contortus: Applications in Drug Discovery.

    PubMed

    Geary, T G

    2016-01-01

    Haemonchus contortus is an important pathogen of small ruminants and is therefore a crucially important target for anthelmintic chemotherapy. Its large size and fecundity have been exploited for the development of in vitro screens for anthelmintic discovery that employ larval and adult stages in several formats. The ability of the parasite to develop to the young adult stage in Mongolian jirds (Meriones unguiculatus) provides a useful small animal model that can be used to screen compounds prior to their evaluation in infected sheep. This chapter summarizes the use of H. contortus for anthelmintic discovery, offers a perspective on current strategies in this area and suggests research challenges that could lead to improvements in the anthelmintic discovery process. PMID:27238010

  9. REDOR NMR for Drug Discovery

    PubMed Central

    Cegelski, Lynette

    2014-01-01

    Rotational-Echo DOuble-Resonance (REDOR) NMR is a powerful and versatile solid-state NMR measurement that has been recruited to elucidate drug modes of action and to drive the design of new therapeutics. REDOR has been implemented to examine composition, structure, and dynamics in diverse macromolecular and whole-cell systems, including taxol-bound microtubules, enzyme-cofactor-inhibitor ternary complexes, and antibiotic-whole-cell complexes. The REDOR approach involves the integrated design of specific isotopic labeling strategies and the selection of appropriate REDOR experiments. By way of example, this digest illustrates the versatility of the REDOR approach, with an emphasis on the practical considerations of experimental design and data interpretation. PMID:24035486

  10. Repurposing strategies for tropical disease drug discovery.

    PubMed

    Klug, Dana M; Gelb, Michael H; Pollastri, Michael P

    2016-06-01

    Neglected tropical diseases (NTDs) and other diseases of the developing world, such as malaria, attract research investments that are disproportionately low compared to their impact on human health worldwide. Therefore, pragmatic methods for launching new drug discovery programs have emerged that repurpose existing chemical matter as new drugs or new starting points for optimization. In this Digest we describe applications of different repurposing approaches for NTDs, and provide a means by which these approaches may be differentiated from each other. These include drug repurposing, target repurposing, target class repurposing, and lead repurposing. PMID:27080183

  11. Pathways to new drug discovery in neuropsychiatry

    PubMed Central

    2012-01-01

    There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success. See related article http://www.biomedcentral.com/1741-7015/10/150 PMID:23194414

  12. Flow Cytometry: Impact On Early Drug Discovery

    PubMed Central

    Edwards, Bruce S.; Sklar, Larry A.

    2015-01-01

    Summary Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens-of-thousands of cells per second and over five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, “sip-and-spit” sampling technology has restricted it to low sample throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens-of-thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multi-parameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry and parallel sample processing promise dramatically expanded single cell profiling capabilities to bolster systems level approaches to drug discovery. PMID:25805180

  13. Flow Cytometry: Impact on Early Drug Discovery.

    PubMed

    Edwards, Bruce S; Sklar, Larry A

    2015-07-01

    Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens of thousands of cells per second and more than five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, "sip-and-spit" sampling technology has restricted it to low-sample-throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens of thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multiparameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage, and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry, and parallel sample processing promise dramatically expanded single-cell profiling capabilities to bolster systems-level approaches to drug discovery. PMID:25805180

  14. Antibacterial drug discovery in the resistance era.

    PubMed

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era. PMID:26791724

  15. Synthetic biology for pharmaceutical drug discovery

    PubMed Central

    Trosset, Jean-Yves; Carbonell, Pablo

    2015-01-01

    Synthetic biology (SB) is an emerging discipline, which is slowly reorienting the field of drug discovery. For thousands of years, living organisms such as plants were the major source of human medicines. The difficulty in resynthesizing natural products, however, often turned pharmaceutical industries away from this rich source for human medicine. More recently, progress on transformation through genetic manipulation of biosynthetic units in microorganisms has opened the possibility of in-depth exploration of the large chemical space of natural products derivatives. Success of SB in drug synthesis culminated with the bioproduction of artemisinin by microorganisms, a tour de force in protein and metabolic engineering. Today, synthetic cells are not only used as biofactories but also used as cell-based screening platforms for both target-based and phenotypic-based approaches. Engineered genetic circuits in synthetic cells are also used to decipher disease mechanisms or drug mechanism of actions and to study cell–cell communication within bacteria consortia. This review presents latest developments of SB in the field of drug discovery, including some challenging issues such as drug resistance and drug toxicity. PMID:26673570

  16. Involvement of Drug Transporters in Organ Toxicity: The Fundamental Basis of Drug Discovery and Development.

    PubMed

    Cheng, Yaofeng; El-Kattan, Ayman; Zhang, Yan; Ray, Adrian S; Lai, Yurong

    2016-04-18

    Membrane transporters play a pivotal role in many organs to maintain their normal physiological functions and contribute significantly to drug absorption, distribution, and elimination. Knowledge gained from gene modified animal models or human genetic disorders has demonstrated that interruption of the transporter activity can lead to debilitating diseases or organ toxicities. Herein we describe transporter associated diseases and organ toxicities resulting from transporter gene deficiency or functional inhibition in the liver, kidney, gastrointestinal tract (GIT), and central nervous system (CNS). While proposing additional transporters as targets for drug-induced organ toxicity, strategies and future perspectives are discussed for transporter risk assessment in drug discovery and development. PMID:26889774

  17. Experiences in fragment-based drug discovery.

    PubMed

    Murray, Christopher W; Verdonk, Marcel L; Rees, David C

    2012-05-01

    Fragment-based drug discovery (FBDD) has become established in both industry and academia as an alternative approach to high-throughput screening for the generation of chemical leads for drug targets. In FBDD, specialised detection methods are used to identify small chemical compounds (fragments) that bind to the drug target, and structural biology is usually employed to establish their binding mode and to facilitate their optimisation. In this article, we present three recent and successful case histories in FBDD. We then re-examine the key concepts and challenges of FBDD with particular emphasis on recent literature and our own experience from a substantial number of FBDD applications. Our opinion is that careful application of FBDD is living up to its promise of delivering high quality leads with good physical properties and that in future many drug molecules will be derived from fragment-based approaches. PMID:22459076

  18. Financing drug discovery for orphan diseases.

    PubMed

    Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

    2014-05-01

    Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. PMID:24269746

  19. Pathology in drug discovery and development.

    PubMed

    Jubb, Adrian M; Koeppen, Hartmut; Reis-Filho, Jorge S

    2014-01-01

    The rapid pace of drug discovery and drug development in oncology, immunology and ophthalmology brings new challenges; the efficient and effective development of new targeted drugs will require more detailed molecular classifications of histologically homogeneous diseases that show heterogeneous clinical outcomes. To this end, single companion diagnostics for specific drugs will be replaced by multiplex diagnostics for entire therapeutic areas, preserving tissue and enabling rapid molecular taxonomy. The field will move away from the development of new molecular entities as single agents, to which resistance is common. Instead, a detailed understanding of the pathological mechanisms of resistance, in patients and in preclinical models, will be key to the validation of scientifically rational and clinically effective drug combinations. To remain at the heart of disease diagnosis and appropriate management, pathologists must evolve into translational biologists and biomarker scientists. Herein, we provide examples of where this metamorphosis has already taken place, in lung cancer and melanoma, where the transformation has yet to begin, in the use of immunotherapies for ophthalmology and oncology, and where there is fertile soil for a revolution in treatment, in efforts to classify glioblastoma and personalize treatment. The challenges of disease heterogeneity, the regulatory environment and adequate tissue are ever present, but these too are being overcome in dedicated academic centres. In summary, the tools necessary to overcome the 'whens' and 'ifs' of the molecular revolution are in the hands of pathologists today; it is a matter of standardization, training and leadership to bring these into routine practice and translate science into patient benefit. This Annual Review Issue of the Journal of Pathology highlights the central role for pathology in modern drug discovery and development. PMID:24122335

  20. Serendipity in Cancer Drug Discovery: Rational or Coincidence?

    PubMed

    Prasad, Sahdeo; Gupta, Subash C; Aggarwal, Bharat B

    2016-06-01

    Novel drug development leading to final approval by the US FDA can cost as much as two billion dollars. Why the cost of novel drug discovery is so expensive is unclear, but high failure rates at the preclinical and clinical stages are major reasons. Although therapies targeting a given cell signaling pathway or a protein have become prominent in drug discovery, such treatments have done little in preventing or treating any disease alone because most chronic diseases have been found to be multigenic. A review of the discovery of numerous drugs currently being used for various diseases including cancer, diabetes, cardiovascular, pulmonary, and autoimmune diseases indicates that serendipity has played a major role in the discovery. In this review we provide evidence that rational drug discovery and targeted therapies have minimal roles in drug discovery, and that serendipity and coincidence have played and continue to play major roles. The primary focus in this review is on cancer-related drug discovery. PMID:27083322

  1. Current Landscape of Antiviral Drug Discovery

    PubMed Central

    Blair, Wade; Cox, Christopher

    2016-01-01

    Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV) and hepatitis B virus (HBV); however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV) and influenza (flu). Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections. PMID:26962437

  2. Matched molecular pair analysis in drug discovery.

    PubMed

    Dossetter, Alexander G; Griffen, Edward J; Leach, Andrew G

    2013-08-01

    Multiple parameter optimisation in drug discovery is difficult, but Matched Molecular Pair Analysis (MMPA) can help. Computer algorithms can process data in an unbiased way to yield design rules and suggest better molecules, cutting the number of design cycles. The approach often makes more suggestions than can be processed manually and methods to deal with this are proposed. However, there is a paucity of contextually specific design rules, which would truly make the technique powerful. By combining extracted information from multiple sources there is an opportunity to solve this problem and advance medicinal chemistry in a matter of months rather than years. PMID:23557664

  3. Financing drug discovery via dynamic leverage.

    PubMed

    Montazerhodjat, Vahid; Frishkopf, John J; Lo, Andrew W

    2016-03-01

    We extend the megafund concept for funding drug discovery to enable dynamic leverage in which the portfolio of candidate therapeutic assets is predominantly financed initially by equity, and debt is introduced gradually as assets mature and begin generating cash flows. Leverage is adjusted so as to maintain an approximately constant level of default risk throughout the life of the fund. Numerical simulations show that applying dynamic leverage to a small portfolio of orphan drug candidates can boost the return on equity almost twofold compared with securitization with a static capital structure. Dynamic leverage can also add significant value to comparable all-equity-financed portfolios, enhancing the return on equity without jeopardizing debt performance or increasing risk to equity investors. PMID:26708982

  4. Spider venomics: implications for drug discovery.

    PubMed

    Pineda, Sandy S; Undheim, Eivind A B; Rupasinghe, Darshani B; Ikonomopoulou, Maria P; King, Glenn F

    2014-10-01

    Over a period of more than 300 million years, spiders have evolved complex venoms containing an extraordinary array of toxins for prey capture and defense against predators. The major components of most spider venoms are small disulfide-bridged peptides that are highly stable and resistant to proteolytic degradation. Moreover, many of these peptides have high specificity and potency toward molecular targets of therapeutic importance. This unique combination of bioactivity and stability has made spider-venom peptides valuable both as pharmacological tools and as leads for drug development. This review describes recent advances in spider-venom-based drug discovery pipelines. We discuss spider-venom-derived peptides that are currently under investigation for treatment of a diverse range of pathologies including pain, stroke and cancer. PMID:25406008

  5. Indoloquinolines as scaffolds for drug discovery.

    PubMed

    Lavrado, J; Moreira, R; Paulo, A

    2010-01-01

    Traditional medicines have contributed greatly over the centuries to the discovery and development of new therapeutic agents and indoloquinoline alkaloids may represent a new class of drug leads. Cryptolepine (5-methyl-5Hindolo[3,2-b]quinoline), neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline), isocryptolepine (5-methyl-5H-indolo[3,2-c]quinoline, extracted from the African medicinal plant Cryptolepis sanguinolenta, and isoneocryptolepine (5-methyl-5Hindolo[2,3-c]quinoline), which has never been found in nature, are isomeric tetracyclic compounds of particular interest due to their broad spectrum of biological activities including antiparasitic, antifungal, antibacterial, cytotoxic, anti-inflammatory and antihyperglycaemic. As a result, in the last 30 years hundreds of indoloquinoline analogues were synthesized and their biological activities evaluated. In this paper, we present an overview of the potential of indoloquinolines as scaffolds in drug discovery by reviewing the in vitro and in vivo biological activities of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships. PMID:20491639

  6. [GWAS of Rheumatoid Arthritis and Drug Discovery].

    PubMed

    Ohmura, Koichiro

    2015-04-01

    We have conducted genome-wide association studies (GWAS) for rheumatoid arthritis (RA). We previously found that myelin basic protein (MBP) is associated with RA. One of the MBP isoforms (Golli-MBP) is expressed not only in nerve cells, but also in hematopoietic cells, and may negatively regulate T-cell receptor signaling. We expanded the GWAS level by collaborating with laboratories in Japan and then throughout the world. Meta-analysis of GWAS data resulted in the identification of -100 genomic loci associated with RA development. The -100 genomic loci contain -400 candidate genes, and it is not easy to find out which genes actually play important roles in RA. By incorporating available public databases, we succeeded in narrowing down the susceptibility genes from 377 to 98. We also showed that regulatory T cells are associated with RA based on the combination of the histone methylation database and our mega-GWAS results. Protein-protein interaction and drug discovery databases gave us information that some of the drugs have already been developed as therapeutic medicines for RA, and some of them were used for diseases other than RA. These drugs may be used for RA in the near future (drug repurposing). The combination of biological databases and GWAS results may be a novel method to identify new therapeutic targets. PMID:26536782

  7. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    PubMed

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry. PMID:23016542

  8. Functional genomics and cancer drug target discovery.

    PubMed

    Moody, Susan E; Boehm, Jesse S; Barbie, David A; Hahn, William C

    2010-06-01

    The recent development of technologies for whole-genome sequencing, copy number analysis and expression profiling enables the generation of comprehensive descriptions of cancer genomes. However, although the structural analysis and expression profiling of tumors and cancer cell lines can allow the identification of candidate molecules that are altered in the malignant state, functional analyses are necessary to confirm such genes as oncogenes or tumor suppressors. Moreover, recent research suggests that tumor cells also depend on synthetic lethal targets, which are not mutated or amplified in cancer genomes; functional genomics screening can facilitate the discovery of such targets. This review provides an overview of the tools available for the study of functional genomics, and discusses recent research involving the use of these tools to identify potential novel drug targets in cancer. PMID:20521217

  9. Toxicology Strategies for Drug Discovery: Present and Future.

    PubMed

    Blomme, Eric A G; Will, Yvonne

    2016-04-18

    Attrition due to nonclinical safety represents a major issue for the productivity of pharmaceutical research and development (R&D) organizations, especially during the compound optimization stages of drug discovery and the early stages of clinical development. Focusing on decreasing nonclinical safety-related attrition is not a new concept, and various approaches have been experimented with over the last two decades. Front-loading testing funnels in Discovery with in vitro toxicity assays designed to rapidly identify unfavorable molecules was the approach adopted by most pharmaceutical R&D organizations a few years ago. However, this approach has also a non-negligible opportunity cost. Hence, significant refinements to the "fail early, fail often" paradigm have been proposed recently to reflect the complexity of accurately categorizing compounds with early data points without taking into account other important contextual aspects, in particular efficacious systemic and tissue exposures. This review provides an overview of toxicology approaches and models that can be used in pharmaceutical Discovery at the series/lead identification and lead optimization stages to guide and inform chemistry efforts, as well as a personal view on how to best use them to meet nonclinical safety-related attrition objectives consistent with a sustainable pharmaceutical R&D model. The scope of this review is limited to small molecules, as large molecules are associated with challenges that are quite different. Finally, a perspective on how several emerging technologies may impact toxicity evaluation is also provided. PMID:26588328

  10. Collaboration for rare disease drug discovery research

    PubMed Central

    Litterman, Nadia K.; Rhee, Michele; Swinney, David C.; Ekins, Sean

    2014-01-01

    Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives. PMID:25685324

  11. From Protein Communication to Drug Discovery.

    PubMed

    Persico, Marco; Di Dato, Antonio; Orteca, Nausicaa; Fattorusso, Caterina; Novellino, Ettore; Andreoli, Mirko; Ferlini, Cristiano

    2015-01-01

    The majority of functionally important biological processes are regulated by allosteric communication within individual proteins and across protein complexes. The proteins controlling these communication networks respond to changes in the cellular environment by switching between different conformational states. Targeting the interface residues mediating these processes through the rational identification of molecules modulating or mimicking their effects holds great therapeutic potential. Protein-protein interactions (PPIs) have shown to have a high degree of plasticity since they occur through small regions, called hot spots, which are included in binding surfaces or in binding clefts of the proteins and are characterized by a high degree of complementarity. This prompted several researchers to compare the protein structure to human grammar proposing terms like "protein language". The decoding of this language represent a new paradigm not only to clarify the dynamics of many biological processes but also to improve the opportunities in drug discovery. In this review, we try to give an overview on intra-molecular and inter-molecular protein communication mechanisms describing the protein interaction domains (PIDs) and short linear motifs (SLiMs), which delineate the authentic syntactic and semantic units in a protein. Moreover, we illustrate some novel approaches performed on natural compounds and on synthetic derivatives aimed at developing new classes of potential drugs able to interfere with intra-molecular and inter-molecular protein communication. PMID:25986690

  12. Computational Drug Repositioning: A Lateral Approach to Traditional Drug Discovery?

    PubMed

    Sahu, Niteshkumar U; Kharkar, Prashant S

    2016-01-01

    Computational drug repositioning is popular in academia and pharmaceutical industry globally. The repositioning hypotheses, generated using a variety of computational methods, can be quickly tested experimentally. Several success stories have emerged in the past decade or so. Newer concepts and methods such as drug profile matching are being tried to address the limitations of current computational repositioning methods. The trend is shifting from earlier small-scale to large-scale or global-scale repositioning applications. Other related approaches such as prediction of molecular targets for novel molecules, prediction of side-effect profiles of new molecular entities (NMEs), etc., are applied routinely. The current article focuses on state-of-the-art of computational drug repositioning field with the help of relevant examples and case studies. This 'lateral' approach has significant potential to bring down the time and cost of the awfully expensive drug discovery research and clinical development. The persistence and perseverance in the successful application of these methods is likely to be paid off in near future. PMID:26881717

  13. Deep sea as a source of novel-anticancer drugs: update on discovery and preclinical/clinical evaluation in a systems medicine perspective.

    PubMed

    Russo, Patrizia; Del Bufalo, Alessandra; Fini, Massimo

    2015-01-01

    The deep-sea habitat is a source of very potent marine-derived agents that may inhibit the growth of human cancer cells "in vitro" and "in vivo". Salinosporamide-A, Marizomib, by Salinispora species is a proteasome inhibitor with promising anticancer activity (Phase I/II trials). Different deep-sea-derived drugs are under preclinical evaluation. Cancer is a complex disease that may be represented by network medicine. A simple consequence is the change of the concept of target entity from a single protein to a whole molecular pathway and or cellular network. Deep-sea-derived drugs fit well to this new concept. PMID:26600744

  14. Deep sea as a source of novel-anticancer drugs: update on discovery and preclinical/clinical evaluation in a systems medicine perspective

    PubMed Central

    Russo, Patrizia; Del Bufalo, Alessandra; Fini, Massimo

    2015-01-01

    The deep-sea habitat is a source of very potent marine-derived agents that may inhibit the growth of human cancer cells “in vitro” and “in vivo”. Salinosporamide-A, Marizomib, by Salinispora species is a proteasome inhibitor with promising anticancer activity (Phase I/II trials). Different deep-sea-derived drugs are under preclinical evaluation. Cancer is a complex disease that may be represented by network medicine. A simple consequence is the change of the concept of target entity from a single protein to a whole molecular pathway and or cellular network. Deep-sea-derived drugs fit well to this new concept. PMID:26600744

  15. Coronaviruses - drug discovery and therapeutic options.

    PubMed

    Zumla, Alimuddin; Chan, Jasper F W; Azhar, Esam I; Hui, David S C; Yuen, Kwok-Yung

    2016-05-01

    In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections. PMID:26868298

  16. Drug discovery from plant sources: An integrated approach

    PubMed Central

    Katiyar, Chandrakant; Gupta, Arun; Kanjilal, Satyajyoti; Katiyar, Shefali

    2012-01-01

    New drug discovery is facing serious challenges due to reduction in number of new drug approvals coupled with exorbitant rising cost. Advent of combinatorial chemistry provided new hope of higher success rates of new chemical entities (NCEs); however, even this scientific development has failed to improve the success rate in new drug discovery. This scenario has prompted us to come out with a novel approach of integrated drug discovery, where Ayurvedic wisdom can synergize with drug discovery from plant sources. Initial steps in new drug discovery involve identification of NCEs, which can be either sourced through chemical synthesis or can be isolated from natural products through biological activity guided fractionation. The sources of many of the new drugs and active ingredients of medicines are derived from natural products. The starting point for plant-based new drug discovery should be identification of the right candidate plants by applying Ayurvedic wisdom, traditional documented use, tribal non-documented use, and exhaustive literature search. Frequency analysis of the ingredients of the ancient documented formulations and analysis of their Ayurvedic attributes may provide an in-depth idea of the predominance of particular Ayurvedic characteristics based on which appropriate candidate plants may be selected for bioactivity-based fractionation. The integration of Ayurvedic wisdom with drug discovery also brings the need for a paradigm shift in the extraction process from sequential to parallel extraction. Bioassay-guided fractionation of the identified plant may lead to standardized extract or isolated bioactive druggable compound as the new drug. This integrated approach would lead to saving of cost and time, coupled with enhanced success rate in drug discovery. PMID:23049178

  17. Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

    PubMed

    Li, Rongshi

    2016-01-01

    Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. PMID:26332654

  18. Leveraging Big Data to Transform Target Selection and Drug Discovery

    PubMed Central

    Chen, B; Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  19. Antimalarial Drug Discovery: From Quinine to the Dream of Eradication

    PubMed Central

    2013-01-01

    The search for antimalarial remedies predates modern medicine and the concept of small molecule chemotherapy, yet has played a central role in the development of both. This history is reviewed in the context of the current renaissance in antimalarial drug discovery, which is seeing modern drug discovery approaches applied to the problem for the first time. Great strides have been made in the past decade, but further innovations from the drug discovery community will be required if the ultimate dream of eradication is to be achieved. PMID:24790706

  20. Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development.

    PubMed

    Bhardwaj, Anshu; Scaria, Vinod; Raghava, Gajendra Pal Singh; Lynn, Andrew Michael; Chandra, Nagasuma; Banerjee, Sulagna; Raghunandanan, Muthukurussi V; Pandey, Vikas; Taneja, Bhupesh; Yadav, Jyoti; Dash, Debasis; Bhattacharya, Jaijit; Misra, Amit; Kumar, Anil; Ramachandran, Srinivasan; Thomas, Zakir; Brahmachari, Samir K

    2011-09-01

    It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. PMID:21782516

  1. CNS Anticancer Drug Discovery and Development Conference White Paper.

    PubMed

    Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C

    2015-11-01

    Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167

  2. Novel opportunities for computational biology and sociology in drug discovery

    PubMed Central

    Yao, Lixia

    2009-01-01

    Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

  3. Assessment of cytochrome p450 enzyme inhibition and inactivation in drug discovery and development.

    PubMed

    Nettleton, David O; Einolf, Heidi J

    2011-01-01

    Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk. PMID:21320066

  4. Pharmacognosy: Science of natural products in drug discovery

    PubMed Central

    Orhan, Ilkay Erdogan

    2014-01-01

    Pharmacognosy deals with the natural drugs obtained from organisms such as most plants, microbes, and animals. Up to date, many important drugs including morphine, atropine, galanthamine, etc. have originated from natural sources which continue to be good model molecules in drug discovery. Traditional medicine is also a part of pharmacognosy and most of the third world countries still depend on the use of herbal medicines. Consequently, pharmacognosy always keeps its popularity in pharmaceutical sciences and plays a critical role in drug discovery. PMID:25337461

  5. High throughput drug discovery with ESI-FTICR

    NASA Astrophysics Data System (ADS)

    Sannes-Lowery, Kristin A.; Cummins, Lendell L.; Chen, Shuo; Drader, Jared J.; Hofstadler, Steven A.

    2004-11-01

    Ribonucleic acids (RNA) are an attractive target for drug discovery since they play critical roles in cellular functions. Because small structured subdomains are known to mimic the behavior of the entire RNA, it is possible to design RNA drug targets that are amenable to interrogation by high performance mass spectrometry. We have developed a high throughput drug discovery platform that uses electrospray ionization Fourier transform ion cyclotron mass spectrometry to investigate ligand binding to structured RNA drug targets. This assay is called multitarget affinity/specificity screening (MASS). Using MASS, we show that it is possible to screen synthetic and natural product libraries in a high throughput and robust manner.

  6. Discoveries in Rubisco: a historical perspective

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Historic discoveries and key observations related to Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), from 1947 to 2006, are presented. Currently, around 200 papers describing Rubisco research are published each year and the literature contains more than 5000 manuscripts on the subject. Wh...

  7. Recent Advances in Drug Repositioning for the Discovery of New Anticancer Drugs

    PubMed Central

    Shim, Joong Sup; Liu, Jun O.

    2014-01-01

    Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and target-based screening assays. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. In this review, recent successful examples of drug repositioning for anticancer drug discovery from non-cancer drugs will be discussed. PMID:25013375

  8. Four disruptive strategies for removing drug discovery bottlenecks.

    PubMed

    Ekins, Sean; Waller, Chris L; Bradley, Mary P; Clark, Alex M; Williams, Antony J

    2013-03-01

    Drug discovery is shifting focus from industry to outside partners and, in the process, creating new bottlenecks. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the USA, with little coordination or consideration of the outputs and creating a translational gap. Although there have been collaborative public-private partnerships in Europe to share pharmaceutical data, the USA has seemingly lagged behind and this may hold it back. Sharing precompetitive data and models may accelerate discovery across the board, while finding the best collaborators, mining social media and mobile approaches to open drug discovery should be evaluated in our efforts to remove drug discovery bottlenecks. We describe four strategies to rectify the current unsustainable situation. PMID:23098820

  9. Systematic discovery of drug interaction mechanisms.

    PubMed

    Chevereau, Guillaume; Bollenbach, Tobias

    2015-04-01

    Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. PMID:25924924

  10. Systematic discovery of drug interaction mechanisms

    PubMed Central

    Chevereau, Guillaume; Bollenbach, Tobias

    2015-01-01

    Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. PMID:25924924

  11. Advances in Nuclear Magnetic Resonance for Drug Discovery

    PubMed Central

    Powers, Robert

    2010-01-01

    Background Drug discovery is a complex and unpredictable endeavor with a high failure rate. Current trends in the pharmaceutical industry have exasperated these challenges and are contributing to the dramatic decline in productivity observed over the last decade. The industrialization of science by forcing the drug discovery process to adhere to assembly-line protocols is imposing unnecessary restrictions, such as short project time-lines. Recent advances in nuclear magnetic resonance are responding to these self-imposed limitations and are providing opportunities to increase the success rate of drug discovery. Objective/Method A review of recent advancements in NMR technology that have the potential of significantly impacting and benefiting the drug discovery process will be presented. These include fast NMR data collection protocols and high-throughput protein structure determination, rapid protein-ligand co-structure determination, lead discovery using fragment-based NMR affinity screens, NMR metabolomics to monitor in vivo efficacy and toxicity for lead compounds, and the identification of new therapeutic targets through the functional annotation of proteins by FAST-NMR. Conclusion NMR is a critical component of the drug discovery process, where the versatility of the technique enables it to continually expand and evolve its role. NMR is expected to maintain this growth over the next decade with advancements in automation, speed of structure calculation, in-cell imaging techniques, and the expansion of NMR amenable targets. PMID:20333269

  12. Single cell analytic tools for drug discovery and development

    PubMed Central

    Heath, James R.; Ribas, Antoni; Mischel, Paul S.

    2016-01-01

    The genetic, functional, or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development.1-3 In cancers, heterogeneity may be essential for tumor stability,4 but its precise role in tumor biology is poorly resolved. This challenges the design of accurate disease models for use in drug development, and can confound the interpretation of biomarker levels, and of patient responses to specific therapies. The complex nature of heterogeneous tissues has motivated the development of tools for single cell genomic, transcriptomic, and multiplex proteomic analysis. We review these tools, assess their advantages and limitations, and explore their potential applications in drug discovery and development. PMID:26669673

  13. G protein-coupled receptors in drug discovery.

    PubMed

    Nambi, Ponnal; Aiyar, Nambi

    2003-04-01

    G protein-coupled receptors (GPCRs) represent one of the most important drug discovery targets such that compounds targeted against GPCRs represent the single largest drug class currently on the market. With the revolutionary advances in human genome sciences and the identification of numerous orphan GPCRs, it is even more important to identify ligands for these orphan GPCRs so that their physiological and pathological roles can be delineated. To this end, major pharmaceutical industries are investing enormous amounts of time and money to achieve this object. This review is a bird's eye view on the various aspects of GPCRs in drug discovery. PMID:15090195

  14. Polypharmacology: drug discovery for the future

    PubMed Central

    Reddy, A. Srinivas

    2013-01-01

    Summary In recent years even with remarkable scientific advancements and significant increase of global R&D spending, drugs are frequently withdrawn from markets. This is primarily due to their side-effects or toxicities. Drug molecules often interact with multiple targets, coined as polypharmacology, and the unintended drug-target interactions could cause side-effects. Polypharmacology remains to be one of the major challenges in drug development, and it opens novel avenues to rationally design next generation of more effective but less toxic therapeutic agents. This review outlines the latest progress and challenges in polypharmacology studies. PMID:23272792

  15. Application of chemical biology in target identification and drug discovery.

    PubMed

    Zhu, Yue; Xiao, Ting; Lei, Saifei; Zhou, Fulai; Wang, Ming-Wei

    2015-09-01

    Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery. PMID:26242900

  16. Use of zebrafish in chemical biology and drug discovery.

    PubMed

    Das, Bhaskar C; McCormick, Laura; Thapa, Pritam; Karki, Radha; Evans, Todd

    2013-11-01

    The zebrafish (Danio rerio) is a small, tropical, freshwater fish that has emerged as a powerful vertebrate model organism for studying genetics and development. Its small size, transparency, cost-effectiveness, close genome homology to humans compared with invertebrates, and capacity for genetic manipulation are all valuable attributes for an excellent animal model. There are additional advantages for using zebrafish specifically in drug discovery, including ease of exposure to chemicals in water. In effect, zebrafish can bridge a gap between in vitro and mammalian work, reducing the use of larger animals and attrition rates. In the drug-discovery process, zebrafish can be used at many stages, including target identification and validation, identification of lead compounds, studying structure-activity relationships and drug safety profiling. In this review, we highlight the potential for the zebrafish model to make the drug-discovery process simpler, more effective and cost-efficient. PMID:24215349

  17. The future for early-stage tuberculosis drug discovery

    PubMed Central

    Zuniga, Edison S; Early, Julie; Parish, Tanya

    2015-01-01

    There is an urgent need for new and better drugs to treat tuberculosis due to lengthy and complex treatment regimens and a rising problem of drug resistance. Drug discovery efforts have increased over the past few years, with a larger focus on modern high-throughput screening technologies. A combination of target-based approaches, with the traditional empirical means of drug identification, has been complemented by the use of target-based phenotypic screens only recently made possibly with newer genetic tools. Using these approaches, a number of promising compound series have been discovered. However, significant problems remain in developing these into drugs. This review highlights recent advances in TB drug discovery, including an overview of screening campaigns, lessons learned and future directions. PMID:25689534

  18. Discovery of plastoquinones: a personal perspective.

    PubMed

    Crane, Frederick L

    2010-03-01

    The discovery and the rediscovery of plastoquinone (PQ) are described together with the definition of its structure as a 2,3-dimethyl 5 solanosyl benzoquinone. The discovery, by M. Kofler, was a result of a search for Vitamin K. Its rediscovery was made by me, when I was at The Enzyme Institute of the University of Wisconsin, analyzing animals and plants for the newly discovered coenzyme Q. In green plants, I found another lipophilic quinone in addition to coenzyme Q. Some misleading evidence suggested as if the new quinone had coenzyme Q activity in mitochondria, but improved methods gave negative results. When I found that the quinone was concentrated in chloroplasts, I considered a role for it in photosynthesis analogous to the role of coenzyme Q in mitochondria. After moving to the Chemistry Department, University of Texas at Austin, I used a plain light bulb and some spinach chloroplasts to show that PQ could be involved in photosynthetic redox reactions. This effect was supported by Norman Bishop's restoration of chloroplast electron transport after solvent extraction, with PQ and photoreduction studies by E. R. Redfern and J. Friend in R. A. Morton's laboratory in Liverpool, UK. We also found an additional analog of PQ in addition to a second analog found in Wisconsin. We called the new analogs PQB and PQC. Although we found some restoration effects with PQC, the discovery by W. T. Griffiths in Morton's laboratory, that PQB and PQC consisted of six forms of PQ each, made it more likely that the new analogs were breakdown products. Morton's group established the structure of the PQCs as a series of PQs, with a hydroxyl group on the prenyl side chain, and the PQB series as having fatty acids esterified to the hydroxyl groups of PQC. Possible functions of the analogs are also discussed in this article. PMID:20217233

  19. Discovery of Novel Antigiardiasis Drug Candidates

    PubMed Central

    Kulakova, Liudmila; Galkin, Andrey; Chen, Catherine Z.; Southall, Noel; Marugan, Juan J.; Zheng, Wei

    2014-01-01

    Giardiasis is a severe intestinal parasitic disease caused by Giardia lamblia, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to G. lamblia trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to in vivo studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-Giardia activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human G. lamblia isolates (assemblages A and B), as determined in in vitro assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was ∼100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails. PMID:25267663

  20. Discovery of novel antigiardiasis drug candidates.

    PubMed

    Kulakova, Liudmila; Galkin, Andrey; Chen, Catherine Z; Southall, Noel; Marugan, Juan J; Zheng, Wei; Herzberg, Osnat

    2014-12-01

    Giardiasis is a severe intestinal parasitic disease caused by Giardia lamblia, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to G. lamblia trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to in vivo studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-Giardia activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human G. lamblia isolates (assemblages A and B), as determined in in vitro assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was ∼ 100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails. PMID:25267663

  1. Highthroughtput analysis of behavior for drug discovery

    PubMed Central

    Alexandrov, Vadim; Brunner, Dani; Hanania, Taleen; Leahy, Emer

    2015-01-01

    Drug testing with traditional behavioral assays constitutes a major bottleneck in the development of novel therapies. PsychoGenics developed three comprehensive highthroughtput systems, SmartCube®, NeuroCube® and PhenoCube® systems, to increase the efficiency of the drug screening and phenotyping in rodents. These three systems capture different domains of behavior, namely, cognitive, motor, circadian, social, anxiety-like, gait and others, using custom-built computer vision software and machine learning algorithms for analysis. This review exemplifies the use of the three systems and explains how they can advance drug screening with their applications to phenotyping of disease models, drug screening, selection of lead candidates, behavior-driven lead optimization, and drug repurposing. PMID:25592319

  2. Animal models of efficacy to accelerate drug discovery in malaria.

    PubMed

    Jiménez-Díaz, María Belén; Viera, Sara; Fernández-Alvaro, Elena; Angulo-Barturen, Iñigo

    2014-01-01

    The emergence of resistance to artemisinins and the renewed efforts to eradicate malaria demand the urgent development of new drugs. In this endeavour, the evaluation of efficacy in animal models is often a go/no go decision assay in drug discovery. This important role relies on the capability of animal models to assess the disposition, toxicology and efficacy of drugs in a single test. Although the relative merits of each efficacy model of malaria as human surrogate have been extensively discussed, there are no critical analyses on the use of such models in current drug discovery. In this article, we intend to analyse how efficacy models are used to discover new antimalarial drugs. Our analysis indicates that testing drug efficacy is often the last assay in each discovery stage and the experimental designs utilized are not optimized to expedite decision-making and inform clinical development. In light of this analysis, we propose new ways to accelerate drug discovery using efficacy models. PMID:23789594

  3. Component architecture in drug discovery informatics.

    PubMed

    Smith, Peter M

    2002-05-01

    This paper reviews the characteristics of a new model of computing that has been spurred on by the Internet, known as Netcentric computing. Developments in this model led to distributed component architectures, which, although not new ideas, are now realizable with modern tools such as Enterprise Java. The application of this approach to scientific computing, particularly in pharmaceutical discovery research, is discussed and highlighted by a particular case involving the management of biological assay data. PMID:12058611

  4. Re-engineering drug discovery and development.

    PubMed

    FitzGerald, Garret A

    2011-10-01

    The rate of new drug approvals in the US has remained essentially constant since 1950, while the costs of drug development have soared. Many commentators question the sustainability of the current model of drug development, in which large pharmaceutical companies incur markedly escalating costs to deliver the same number of products to market. This Issue Brief summarizes the problem, describes ongoing governmental efforts to influence the process, and suggests changes in regulatory science and translational medicine that may promote more successful development of safe and effective therapeutics PMID:22049582

  5. The changing landscape of antiparasitic drug discovery for veterinary medicine.

    PubMed

    Geary, Timothy G; Conder, George A; Bishop, Bernard

    2004-10-01

    Changes in economic imperatives in the pharmaceutical industry have led to a wave of consolidation, which has had the unintended side effect of shrinking the resource devoted to antiparasitic drug discovery in animal health companies. Scientific changes have altered the way in which drugs could be discovered in the future. New science and business models will need to be implemented to address the demand for innovative antiparasitic drugs in veterinary medicine. Novel drugs are needed to combat drug resistance and for currently non-addressed problems. At the center of the future for this field, however, lies the need for more support into the basic research on the biology of parasites. PMID:15363437

  6. C. elegans in high-throughput drug discovery

    PubMed Central

    O’Reilly, Linda P.; Luke, Cliff J.; Perlmutter, David H.; Silverman, Gary A.; Pak, Stephen C.

    2014-01-01

    C. elegans has proven to be a useful model organism for investigating molecular and cellular aspects of numerous human diseases. More recently, investigators have explored the use of this organism as a tool for drug discovery. Although earlier drug screens were labor-intensive and low in throughput, recent advances in high-throughput liquid workflows, imaging platforms and data analysis software have made C. elegans a viable option for automated high-throughput drug screens. This review will outline the evolution of C. elegans-based drug screening, discuss the inherent challenges of using C. elegans, and highlight recent technological advances that have paved the way for future drug screens. PMID:24333896

  7. Recent advances in malaria drug discovery

    PubMed Central

    Biamonte, Marco A.; Wanner, Jutta; Le Roch, Karine G.

    2013-01-01

    This digest covers some of the most relevant progress in malaria drug disco very published betwe en 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug disco very efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria. PMID:23587422

  8. Drug discovery: Fighting evolution with chemical synthesis

    NASA Astrophysics Data System (ADS)

    Yan, Ming; Baran, Phil S.

    2016-05-01

    A synthetic strategy has been developed that provides easy access to structurally diverse analogues of naturally occurring antibiotics, providing a fresh means of attack in the war against drug-resistant bacteria. See Article p.338

  9. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.

    PubMed

    Bauer, Renato A

    2015-09-01

    Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease. PMID:26002380

  10. Benefits of Structural Genomics for Drug Discovery Research

    SciTech Connect

    Grabowski, M.; Chruszcz, M; Zimmerman, M; Kirillova, O; Minor, W

    2009-01-01

    While three dimensional structures have long been used to search for new drug targets, only a fraction of new drugs coming to the market has been developed with the use of a structure-based drug discovery approach. However, the recent years have brought not only an avalanche of new macromolecular structures, but also significant advances in the protein structure determination methodology only now making their way into structure-based drug discovery. In this paper, we review recent developments resulting from the Structural Genomics (SG) programs, focusing on the methods and results most likely to improve our understanding of the molecular foundation of human diseases. SG programs have been around for almost a decade, and in that time, have contributed a significant part of the structural coverage of both the genomes of pathogens causing infectious diseases and structurally uncharacterized biological processes in general. Perhaps most importantly, SG programs have developed new methodology at all steps of the structure determination process, not only to determine new structures highly efficiently, but also to screen protein/ligand interactions. We describe the methodologies, experience and technologies developed by SG, which range from improvements to cloning protocols to improved procedures for crystallographic structure solution that may be applied in 'traditional' structural biology laboratories particularly those performing drug discovery. We also discuss the conditions that must be met to convert the present high-throughput structure determination pipeline into a high-output structure-based drug discovery system.

  11. Drug discovery: new models for industry-academic partnerships.

    PubMed

    Tralau-Stewart, Cathy J; Wyatt, Colin A; Kleyn, Dominique E; Ayad, Alex

    2009-01-01

    The re-focusing of pharmaceutical industry research away from early discovery activities is stimulating the development of novel models of drug discovery, notably involving academia as a 'front end'. In this article the authors explore the drivers of change, the role of new entrants (universities with specialised core facilities) and novel partnership models. If they are to be sustainable and deliver, these new models must be flexible and properly funded by industry or public funding, rewarding all partners for contributions. The introduction of an industry-like process and experienced management teams signals a revolution in discovery that benefits society by improving the value gained from publicly funded research. PMID:18992364

  12. The JAK kinases: not just another kinase drug discovery target.

    PubMed

    Wilks, Andrew F

    2008-08-01

    There are four members of the JAK family of protein tyrosine kinases (PTKs) in the human genome. Since their discovery in 1989, great strides have been made in the understanding of their role in normal intracellular signalling. Importantly, their roles in pathologies ranging from cancer to immune deficiencies have placed them front and centre as potential drug targets. The recent discovery of the role of activating mutations in the kinase-like domain (KLD) of JAK2 in the development of polycythemia rubra vera, and the elaboration of KLD mutation as a broader mechanism by which cells might become hyperproliferative has sparked enormous interest in the development of JAK selective drug candidates. I review herein the progress that has been made in the discovery of JAK-targeted inhibitors, and discuss the challenges that face the development of these drugs for use in the clinic. PMID:18721891

  13. Nature’s bounty – drug discovery from the sea

    PubMed Central

    Bowling, John J; Kochanowska, Anna J; Kasanah, Noer; Hamann, Mark T

    2016-01-01

    With ~ 40 years of research completed after the development of self-contained underwater breathing apparatus, drug discovery opportunities in the sea are still too numerous to count. Since the FDA approval of the direct-from-the-sea calcium channel blocker ziconotide, marine natural products have been validated as a source for new medicines. However, the demand for natural products is extremely high due to the development of high-throughput assays and this bottleneck has created the need for an intense focus on increasing the rate of isolating and elucidating the structures of new bioactive secondary metabolites. In addition to highlighting the drug discovery potential of the marine environment, this review discusses several of the pressing needs to increase the rate of drug discovery in marine natural products, and describes some of the work and new technologies that are contributing in this regard. PMID:23484601

  14. Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends.

    PubMed

    Zhan, Peng; Pannecouque, Christophe; De Clercq, Erik; Liu, Xinyong

    2016-04-14

    The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus. PMID:26509831

  15. Developing doctoral scientists for drug discovery: pluridimensional education required.

    PubMed

    Janero, David R

    2013-02-01

    Research universities continue to produce new scientists capable of generating knowledge with the potential to inform disease etiology and treatment. Mounting interest of doctoral-level experimental science students in therapeutics-related research careers is discordant with the widespread lack of direct drug-discovery and development experience, let alone commercialization success, among university faculty and administrators. Likewise, the archetypical publication- and grant-fueled, principal investigator (PI)-focused academic system ("PI-stan") risks commoditization of science students pursuing their doctorates as a labor source, rendering them ill-prepared for career options related to therapeutics innovation by marginalizing their development of "beyond-the-bench" professional skills foundational to modern drug-discovery campaigns and career fluency. To militate against professionalization deficits in doctoral drug-discovery researchers, the author--a scientist-administrator-consultant with decades of discovery research and development (R&D), business, and educator experience in commercial and university settings--posits a critical need for pluridimensionality in graduate education and mentorship that extends well beyond thesis-related scientific domains/laboratory techniques to instill transferable operational-intelligence, project/people-management, and communication competencies. Specific initiatives are advocated to help enhance the doctoral science student's market competitiveness, adaptability, and navigation of the significant research, commercial, and occupational challenges associated with contemporary preclinical drug-discovery R&D. PMID:23231364

  16. De Novo Fragment Design for Drug Discovery and Chemical Biology.

    PubMed

    Rodrigues, Tiago; Reker, Daniel; Welin, Martin; Caldera, Michael; Brunner, Cyrill; Gabernet, Gisela; Schneider, Petra; Walse, Björn; Schneider, Gisbert

    2015-12-01

    Automated molecular de novo design led to the discovery of an innovative inhibitor of death-associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment-like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery. PMID:26486226

  17. Drug Discovery in an Academic Setting: Playing to the Strengths

    PubMed Central

    2013-01-01

    Drug discovery and medicinal chemistry initiatives in academia provide an opportunity to create a unique environment that is distinct from the traditional industrial model. Two characteristics of a university setting that are not usually associated with pharma are the ability to pursue high-risk projects and a depth of expertise, infrastructure, and capabilities in focused areas. Encouraging, supporting, and fostering drug discovery efforts that take advantage of these and other distinguishing characteristics of an academic setting can lead to novel and innovative therapies that might not be discovered otherwise. PMID:24900665

  18. Fragment-Based Drug Discovery Using NMR Spectroscopy

    PubMed Central

    Harner, Mary J.; Frank, Andreas O.; Fesik, Stephen W.

    2013-01-01

    Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable identification of small molecules that bind to proteins and for hit-to-lead optimization. Here, we describe the use of NMR spectroscopy as a method for fragment-based drug discovery and how to most effectively utilize this approach for discovering novel therapeutics based on our experience. PMID:23686385

  19. Visceral leishmaniasis: experimental models for drug discovery.

    PubMed

    Gupta, Suman

    2011-01-01

    Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality. The causative agent is a haemoflagellate protozoan Leishmania donovani, an obligate intracellular parasite that resides and multiplies within macrophages of the reticulo-endothelial system. Most of the existing anti-leishmanial drugs have serious side effects that limit their clinical application. As an alternate strategy, vaccination is also under experimental and clinical trials. The in vitro evaluation designed to facilitate rapid testing of a large number of drugs has been focussed on the promastigotes milt little attention on the clinically relevant parasite stage, amastigotes. Screening designed to closely reflect the situation in vivo is currently time consuming, laborious, and expensive, since it requires intracellular amastigotes and animal model. The ability to select transgenic Leishmania expressing reporter proteins, such as the green fluorescent proteins (GFP) or the luciferase opened up new possibilities for the development of drug screening models. Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans. Available in vitro and in vivo methodologies for antileishmanial drug screening and their respective advantages and disadvantages are reviewed. PMID:21321417

  20. [Activity of NTDs Drug-discovery Research Consortium].

    PubMed

    Namatame, Ichiji

    2016-01-01

    Neglected tropical diseases (NTDs) are an extremely important issue facing global health care. To improve "access to health" where people are unable to access adequate medical care due to poverty and weak healthcare systems, we have established two consortiums: the NTD drug discovery research consortium, and the pediatric praziquantel consortium. The NTD drug discovery research consortium, which involves six institutions from industry, government, and academia, as well as an international non-profit organization, is committed to developing anti-protozoan active compounds for three NTDs (Leishmaniasis, Chagas disease, and African sleeping sickness). Each participating institute will contribute their efforts to accomplish the following: selection of drug targets based on information technology, and drug discovery by three different approaches (in silico drug discovery, "fragment evolution" which is a unique drug designing method of Astellas Pharma, and phenotypic screening with Astellas' compound library). The consortium has established a brand new database (Integrated Neglected Tropical Disease Database; iNTRODB), and has selected target proteins for the in silico and fragment evolution drug discovery approaches. Thus far, we have identified a number of promising compounds that inhibit the target protein, and we are currently trying to improve the anti-protozoan activity of these compounds. The pediatric praziquantel consortium was founded in July 2012 to develop and register a new praziquantel pediatric formulation for the treatment of schistosomiasis. Astellas Pharma has been a core member in this consortium since its establishment, and has provided expertise and technology in the area of pediatric formulation development and clinical development. PMID:26831798

  1. Prospects for neurodegenerative and psychiatric disorder drug discovery.

    PubMed

    Williams, Michael; Enna, S J

    2011-05-01

    The discovery of CNS-active drugs has, to a major extent, resulted from clinical serendipity. Once targets for such compounds were identified, conventional mechanism-based approaches were used to identify new chemical entities for the treatment of neurological and psychiatric disorders. Most of these have, however, failed to display any greater efficacy than existing psychotherapeutics and may, in fact, be less efficacious because of side effect liabilities. Among the reasons for this lack of success in drug discovery include a lack of fundamental knowledge regarding the causes of CNS disorders, the absence of biomarkers for diagnosing and monitoring these conditions, a paucity of animal models that are congruent with the human disease state and the increasing likelihood that CNS conditions are multifactorial in their etiology. These challenges force the inclusion of a Phase IIa proof of concept trial as a component of the drug discovery program. Unlike other therapeutic areas, serendipity is a major factor in the CNS translational medicine interface requiring a close collaboration between preclinical and clinical scientists trained to appreciate unusual behavioral phenotypes. When combined with conventional target-based drug discovery technologies, this increases the likelihood of identifying truly novel drugs for the treatment of CNS disorders. PMID:22646072

  2. Impact of Quaternary Structure Dynamics on Allosteric Drug Discovery

    PubMed Central

    Jaffe, Eileen K.

    2013-01-01

    The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131–143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics. PMID:23409765

  3. Membrane lipidomics for the discovery of new antiparasitic drug targets.

    PubMed

    Maréchal, Eric; Riou, Mickaël; Kerboeuf, Dominique; Beugnet, Frédéric; Chaminade, Pierre; Loiseau, Philippe M

    2011-11-01

    Advances in lipid separation methods and mass spectrometry technologies allow the fine characterization of the lipidome of parasites, ranging from unicellular protists to worms, which cause threatening infections in vertebrates, including humans. Specific lipid structures or lipid metabolic pathways can inspire the development of novel antiparasitic drugs. Changes in the lipid balance in membranes of parasites can also provide clues on the dynamics of drugs and some mechanisms of drug resistance. This review highlights recent trends in parasite lipidomics, combined with functional analyses, for the discovery of novel targets and the development of novel drugs. PMID:21862412

  4. CANDO and the infinite drug discovery frontier

    PubMed Central

    Minie, Mark; Chopra, Gaurav; Sethi, Geetika; Horst, Jeremy; White, George; Roy, Ambrish; Hatti, Kaushik; Samudrala, Ram

    2014-01-01

    The Computational Analysis of Novel Drug Opportunities (CANDO) platform (http://protinfo.org/cando) uses similarity of compound–proteome interaction signatures to infer homology of compound/drug behavior. We constructed interaction signatures for 3733 human ingestible compounds covering 48,278 protein structures mapping to 2030 indications based on basic science methodologies to predict and analyze protein structure, function, and interactions developed by us and others. Our signature comparison and ranking approach yielded benchmarking accuracies of 12–25% for 1439 indications with at least two approved compounds. We prospectively validated 49/82 ‘high value’ predictions from nine studies covering seven indications, with comparable or better activity to existing drugs, which serve as novel repurposed therapeutics. Our approach may be generalized to compounds beyond those approved by the FDA, and can also consider mutations in protein structures to enable personalization. Our platform provides a holistic multiscale modeling framework of complex atomic, molecular, and physiological systems with broader applications in medicine and engineering. PMID:24980786

  5. New avenues for anti-epileptic drug discovery and development.

    PubMed

    Löscher, Wolfgang; Klitgaard, Henrik; Twyman, Roy E; Schmidt, Dieter

    2013-10-01

    Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs. PMID:24052047

  6. Solid-Phase Biological Assays for Drug Discovery

    NASA Astrophysics Data System (ADS)

    Forsberg, Erica M.; Sicard, Clémence; Brennan, John D.

    2014-06-01

    In the past 30 years, there has been a significant growth in the use of solid-phase assays in the area of drug discovery, with a range of new assays being used for both soluble and membrane-bound targets. In this review, we provide some basic background to typical drug targets and immobilization protocols used in solid-phase biological assays (SPBAs) for drug discovery, with emphasis on particularly labile biomolecular targets such as kinases and membrane-bound receptors, and highlight some of the more recent approaches for producing protein microarrays, bioaffinity columns, and other devices that are central to small molecule screening by SPBA. We then discuss key applications of such assays to identify drug leads, with an emphasis on the screening of mixtures. We conclude by highlighting specific advantages and potential disadvantages of SPBAs, particularly as they relate to particular assay formats.

  7. Barriers to Alzheimer disease drug discovery and development in academia.

    PubMed

    Van Eldik, Linda J; Koppal, Tanuja; Watterson, D Martin

    2002-01-01

    The drug discovery and the drug development processes represent a continuum of recursive activities that range from initial drug target identification to final Food and Drug Administration approval and marketing of a new therapeutic. Drug discovery, as its name implies, is more exploratory and less focused in many cases, whereas drug development has a clinically defined endpoint and a specific disease goal. Academia has historically made major contributions to this process at the early discovery phases. However, current trends in the organization of the pharmaceutical industry suggest an expanded role for academia in the near future. Megamergers among major pharmaceutical corporations indicate their movement toward a focus on end-stage clinical trials, manufacturing, and marketing. There has been a parallel increase in outsourcing of intermediate steps to specialty small pharmaceutical, biotechnology, and contract service companies. The new paradigm suggests that academia will play an increasingly important role at the proof-of-principle stage of basic and clinical drug discovery research, in training the future skilled work force, and in close partnerships with small pharmaceutical and biotechnology companies. However, academic drug discovery research faces a set of barriers to progress, the relative importance of which varies with the home institution and the details of the research area. These barriers fall into four general categories: (1) the historical administrative structure and environment of academia; (2) the structure and emphasis of peer review panels that control research funding by government and private agencies; (3) the organization and operation of the academic infrastructure; and (4) the structure and availability of specialized resources and information management. Selected examples of barriers to drug discovery and drug development research and training in academia are presented, as are some specific recommendations designed to minimize or

  8. Discovery of small molecule cancer drugs: Successes, challenges and opportunities

    PubMed Central

    Hoelder, Swen; Clarke, Paul A.; Workman, Paul

    2012-01-01

    The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the ‘Valley of Death’ between basic research and approved medicines. We envisage a future in which addressing these challenges will

  9. Drug discovery and development for neglected diseases: the DNDi model.

    PubMed

    Chatelain, Eric; Ioset, Jean-Robert

    2011-01-01

    New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness), leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public-private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi's own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven. PMID:21552487

  10. Third Generation Sequencing Techniques and Applications to Drug Discovery

    PubMed Central

    Ozsolak, Fatih

    2012-01-01

    Introduction There is an immediate need for functional and molecular studies to decipher differences between disease and “normal” settings to identify large quantities of validated targets with the highest therapeutic utilities. Furthermore, drug mechanism of action and biomarkers to predict drug efficacy and safety need to be identified for effective design of clinical trials, decreasing attrition rates, regulatory agency approval process and drug repositioning. By expanding the power of genetics and pharmacogenetics studies, next generation nucleic acid sequencing technologies have started to play an important role in all stages of drug discovery. Areas covered This article reviews the first and second generation sequencing technologies (SGSTs) and challenges they pose to biomedicine. The article then focuses on the emerging third generation sequencing technologies (TGSTs), their technological foundations and potential contributions to drug discovery. Expert Opinion Despite the scientific and commercial success of SGSTs, the goal of rapid, comprehensive and unbiased sequencing of nucleic acids has not been achieved. TGSTs promise to increase sequencing throughput and read lengths, decrease costs, run times and error rates, eliminate biases inherent in SGSTs, and offer capabilities beyond nucleic acid sequencing. Such changes will have positive impact in all sequencing applications to drug discovery. PMID:22468954

  11. Systems Biology Approaches to a Rational Drug Discovery Paradigm.

    PubMed

    Prathipati, Philip; Mizuguchi, Kenji

    2016-01-01

    Ligand- and structure-based drug design approaches complement phenotypic and target screens, respectively, and are the two major frameworks for guiding early-stage drug discovery efforts. Since the beginning of this century, the advent of the genomic era has presented researchers with a myriad of high throughput biological data (parts lists and their interaction networks) to address efficacy and toxicity, augmenting the traditional ligand- and structure-based approaches. This data rich era has also presented us with challenges related to integrating and analyzing these multi-platform and multi-dimensional datasets and translating them into viable hypotheses. Hence in the present paper, we review these existing approaches to drug discovery research and argue the case for a new systems biology based approach. We present the basic principles and the foundational arguments/underlying assumptions of the systems biology based approaches to drug design. Also discussed are systems biology data types (key entities, their attributes and their relationships with each other, and data models/representations), software and tools used for both retrospective and prospective analysis, and the hypotheses that can be inferred. In addition, we summarize some of the existing resources for a systems biology based drug discovery paradigm (open TG-GATEs, DrugMatrix, CMap and LINCs) in terms of their strengths and limitations. PMID:26306988

  12. From bench to patient: model systems in drug discovery.

    PubMed

    Breyer, Matthew D; Look, A Thomas; Cifra, Alessandra

    2015-10-01

    Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides. PMID:26438689

  13. Preclinical Pharmacological Approaches in Drug Discovery for Chronic Pain.

    PubMed

    Whiteside, Garth T; Pomonis, James D; Kennedy, Jeffrey D

    2016-01-01

    In recent years, animal behavioral models, particularly those used in pain research, have been increasingly scrutinized and criticized for their role in the poor translation of novel pharmacotherapies for chronic pain. This chapter addresses the use of animal models of pain used in drug discovery research. It highlights how, when, and why animal models of pain are used as one of the many experimental tools used to gain better understanding of target mechanisms and rank-order compounds in the iterative process of establishing structure-activity relationship. Together, these models help create an "analgesic signature" for a compound and inform the indications most likely to yield success in clinical trials. In addition, the authors discuss some often underappreciated aspects of currently used (traditional) animal models of pain, including simply applying basic pharmacological principles to study design and data interpretation as well as consideration of efficacy alongside side effect measures as part of the overall conclusion of efficacy. This is provided to add perspective regarding current efforts to develop new models and endpoints both in rodents and in larger animal species as well as assess cognitive and/or affective aspects of pain. Finally, the authors suggest ways in which efficacy evaluation in animal models of pain, whether traditional or new, might better align with clinical standards of analysis, citing examples where applying effect size and number needed to treat estimations to animal model data suggest that the efficacy bar often may be set too low preclinically to allow successful translation to the clinical setting. PMID:26920017

  14. Competitive intelligence and patent analysis in drug discovery.

    PubMed

    Grandjean, Nicolas; Charpiot, Brigitte; Pena, Carlos Andres; Peitsch, Manuel C

    2005-01-01

    Patents are a major source of information in drug discovery and, when properly processed and analyzed, can yield a wealth of information on competitors activities, R&D trends, emerging fields, collaborations, among others. This review discusses the current state-of-the-art in textual data analysis and exploration methods as applied to patent analysis.: PMID:24981938

  15. Aprepitant: drug-drug interactions in perspective.

    PubMed

    Aapro, M S; Walko, C M

    2010-12-01

    The implications of chemotherapeutic drug-drug interactions can be serious and thus need to be addressed. This review concerns the potential interactions of the antiemetic aprepitant, a neurokinin-1 receptor antagonist indicated for use (in Europe) in highly emetogenic chemotherapy and moderately emetogenic chemotherapy (MEC) in combination with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and corticosteroids and (in the United States) in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high-dose cisplatin. When considering use of aprepitant for prevention of chemotherapy-induced nausea and vomiting, its potential drug-drug interaction profile as a moderate inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4) has been a source of concern for some physicians and other health care professionals. We explore in this paper how real those concerns are. Our conclusion is that either no interaction or no clinically relevant interaction exists with chemotherapeutic agents (intravenous cyclophosphamide, docetaxel, intravenous vinorelbine) or 5-HT3 antagonists (granisetron, ondansetron, palonosetron). For relevant interactions, appropriate measures, such as corticosteroid dose modifications and extended International Normalized Ratio monitoring of patients on warfarin therapy, can be taken to effectively manage them. Therefore, the concern of negative interactions remains largely theoretical but needs to be verified with new agents extensively metabolized through the 3A4 pathway. PMID:20488873

  16. Role of Molecular Dynamics and Related Methods in Drug Discovery.

    PubMed

    De Vivo, Marco; Masetti, Matteo; Bottegoni, Giovanni; Cavalli, Andrea

    2016-05-12

    Molecular dynamics (MD) and related methods are close to becoming routine computational tools for drug discovery. Their main advantage is in explicitly treating structural flexibility and entropic effects. This allows a more accurate estimate of the thermodynamics and kinetics associated with drug-target recognition and binding, as better algorithms and hardware architectures increase their use. Here, we review the theoretical background of MD and enhanced sampling methods, focusing on free-energy perturbation, metadynamics, steered MD, and other methods most consistently used to study drug-target binding. We discuss unbiased MD simulations that nowadays allow the observation of unsupervised ligand-target binding, assessing how these approaches help optimizing target affinity and drug residence time toward improved drug efficacy. Further issues discussed include allosteric modulation and the role of water molecules in ligand binding and optimization. We conclude by calling for more prospective studies to attest to these methods' utility in discovering novel drug candidates. PMID:26807648

  17. Emerging applications of metabolomics in drug discovery and precision medicine.

    PubMed

    Wishart, David S

    2016-07-01

    Metabolomics is an emerging 'omics' science involving the comprehensive characterization of metabolites and metabolism in biological systems. Recent advances in metabolomics technologies are leading to a growing number of mainstream biomedical applications. In particular, metabolomics is increasingly being used to diagnose disease, understand disease mechanisms, identify novel drug targets, customize drug treatments and monitor therapeutic outcomes. This Review discusses some of the latest technological advances in metabolomics, focusing on the application of metabolomics towards uncovering the underlying causes of complex diseases (such as atherosclerosis, cancer and diabetes), the growing role of metabolomics in drug discovery and its potential effect on precision medicine. PMID:26965202

  18. Drug Normalization for Cancer Therapeutic and Druggable Genome Target Discovery

    PubMed Central

    Jiang, Guoqian; Sohn, Sunghwan; Zimmermann, Michael T.; Wang, Chen; Liu, Hongfang; Chute, Christopher G.

    2015-01-01

    Heterogeneous drug data representation among different druggable genome knowledge resources and datasets delays effective cancer therapeutic target discovery within the broad scientific community. The objective of the present paper is to describe the challenges and lessons learned from our efforts in developing and evaluating a standards-based drug normalization framework targeting cancer druggable genome datasets. Our findings suggested that mechanisms need to be established to deal with spelling errors and irregularities in normalizing clinical drug data in The Cancer Genome Atlas (TCGA), whereas the annotations from NCI Thesaurus (NCIt) and PubChem are two layers of normalization that potentially bridge between the clinical phenotypes and the druggable genome knowledge for effective cancer therapeutic target discovery. PMID:26306243

  19. Organs-on-chips at the frontiers of drug discovery

    PubMed Central

    Esch, Eric W.; Bahinski, Anthony; Huh, Dongeun

    2016-01-01

    Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology. PMID:25792263

  20. Twenty years on: the impact of fragments on drug discovery.

    PubMed

    Erlanson, Daniel A; Fesik, Stephen W; Hubbard, Roderick E; Jahnke, Wolfgang; Jhoti, Harren

    2016-09-01

    After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts. PMID:27417849

  1. Medicinal chemistry inspired fragment-based drug discovery.

    PubMed

    Lanter, James; Zhang, Xuqing; Sui, Zhihua

    2011-01-01

    Lead generation can be a very challenging phase of the drug discovery process. The two principal methods for this stage of research are blind screening and rational design. Among the rational or semirational design approaches, fragment-based drug discovery (FBDD) has emerged as a useful tool for the generation of lead structures. It is particularly powerful as a complement to high-throughput screening approaches when the latter failed to yield viable hits for further development. Engagement of medicinal chemists early in the process can accelerate the progression of FBDD efforts by incorporating drug-friendly properties in the earliest stages of the design process. Medium-chain acyl-CoA synthetase 2b and ketohexokinase are chosen as examples to illustrate the importance of close collaboration of medicinal chemists, crystallography, and modeling. PMID:21371600

  2. Drug discovery in focal and segmental glomerulosclerosis.

    PubMed

    Pullen, Nick; Fornoni, Alessia

    2016-06-01

    Despite the high medical burden experienced by patients with focal segmental glomerulosclerosis, the etiology of the condition remains largely unknown. Focal segmental glomerulosclerosis is highly heterogeneous in clinical and morphologic manifestations. While this presents challenges for the development of new treatments, research investments over the last 2 decades have yielded a surfeit of potential avenues for therapeutic intervention. The development of many of those ideas and concepts into new therapies, however, has been very disappointing. Here, we describe some of the factors that have potentially contributed to the poor translational performance from this research investment, including the confidence we ascribe to a target, the conduct of experimental studies, and the availability of selective reagents to test hypotheses. We will discuss the significance of genetic and systems traits as well as other methods for reducing bias. We will analyze the limitations of a successful drug development. We will use specific examples hoping that these will guide a consensus for investment and drive greater translational quality. We hope that this substrate will serve to exemplify the tremendous opportunity for intervention as well as facilitate greater collaborative effort between industry, academia, and private foundations in promoting appropriate validation of these targets. Only then will we have achieved our goal for curative therapies for this devastating disease. PMID:27165834

  3. Progressive MS: from pathophysiology to drug discovery.

    PubMed

    Salvetti, Marco; Landsman, Douglas; Schwarz-Lam, Peter; Comi, Giancarlo; Thompson, Alan J; Fox, Robert J

    2015-10-01

    Progressive multiple sclerosis (MS) will be a major area of research interest for years to come. No treatments exist and success in the field will generalise to other neurological conditions where neurodegeneration coexists with neuroinflammation. The issue is complex, and interdisciplinary approaches - uniting scientists with different competences (neurobiology, immunogenetics, etc.) and 'mindsets' (academia and industry) - will be decisive. The International Progressive MS Alliance is catalysing this process through various initiatives, the most recent of which was a meeting where scientists from academia (also outside the MS field) and from industry reviewed data and strategies to determine the next steps towards the translation of current knowledge into effective therapies.Key findings are:(i). Concerted efforts are essential to prioritise pathogenetic mechanisms according to impact on the disease and druggability.(ii). Combination therapies will probably be needed, possibly early in the disease, along with new trial designs and treatment schedules.(iii). Drug screenings are a pragmatic approach hopefully enriched by the use of neural and oligodendrocyte progenitors differentiated from induced pluripotent stem cells (iPSCs).(iv). The field of network biology will increase our ability to predict therapeutic targets.(v). Genome-wide association studies (GWAS) must try to identify variants associated with disease progression. PMID:26362902

  4. Using DrugBank for In Silico Drug Exploration and Discovery.

    PubMed

    Wishart, David S; Wu, Anthony

    2016-01-01

    DrugBank is a fully curated drug and drug target database that contains 8174 drug entries including 1944 FDA approved small-molecule drugs, 198 FDA-approved biotech (protein/peptide) drugs, 93 nutraceuticals, and over 6000 experimental drugs. Additionally, 4300 non-redundant protein (i.e., drug target/enzyme/transporter/carrier) sequences are linked to these drug entries. DrugBank is primarily focused on providing both the query/search tools and biophysical data needed to facilitate drug discovery and drug development. This unit provides readers with a detailed description of how to effectively use the DrugBank database and how to navigate through the DrugBank Web site. It also provides specific examples of how to find chemical homologs of potential drug leads and how to identify potential drug targets from newly sequenced tumor samples. The intent of this unit is to give readers an introduction to the field of Web-based drug discovery and to show how cheminformatics can be seamlessly integrated into the field of bioinformatics. © 2016 by John Wiley & Sons, Inc. PMID:27322405

  5. The tuberculosis drug discovery and development pipeline and emerging drug targets.

    PubMed

    Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

    2015-06-01

    The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061

  6. Cloud computing approaches to accelerate drug discovery value chain.

    PubMed

    Garg, Vibhav; Arora, Suchir; Gupta, Chitra

    2011-12-01

    Continued advancements in the area of technology have helped high throughput screening (HTS) evolve from a linear to parallel approach by performing system level screening. Advanced experimental methods used for HTS at various steps of drug discovery (i.e. target identification, target validation, lead identification and lead validation) can generate data of the order of terabytes. As a consequence, there is pressing need to store, manage, mine and analyze this data to identify informational tags. This need is again posing challenges to computer scientists to offer the matching hardware and software infrastructure, while managing the varying degree of desired computational power. Therefore, the potential of "On-Demand Hardware" and "Software as a Service (SAAS)" delivery mechanisms cannot be denied. This on-demand computing, largely referred to as Cloud Computing, is now transforming the drug discovery research. Also, integration of Cloud computing with parallel computing is certainly expanding its footprint in the life sciences community. The speed, efficiency and cost effectiveness have made cloud computing a 'good to have tool' for researchers, providing them significant flexibility, allowing them to focus on the 'what' of science and not the 'how'. Once reached to its maturity, Discovery-Cloud would fit best to manage drug discovery and clinical development data, generated using advanced HTS techniques, hence supporting the vision of personalized medicine. PMID:21843145

  7. Drug discovery for alopecia: gone today, hair tomorrow

    PubMed Central

    Santos, Zenildo; Avci, Pinar; Hamblin, Michael R

    2015-01-01

    Introduction Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. Areas covered In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8+NK group 2D-positive (NKG2D+) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. Expert opinion The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play. PMID:25662177

  8. Drug Discovery Prospect from Untapped Species: Indications from Approved Natural Product Drugs

    PubMed Central

    Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Zhang, Cun Long; Tan, Chun Yan; Chen, Yu Zong; Jiang, Yu Yang

    2012-01-01

    Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery. PMID:22808057

  9. Drug Repurposing from an Academic Perspective.

    PubMed

    Oprea, Tudor I; Bauman, Julie E; Bologa, Cristian G; Buranda, Tione; Chigaev, Alexandre; Edwards, Bruce S; Jarvik, Jonathan W; Gresham, Hattie D; Haynes, Mark K; Hjelle, Brian; Hromas, Robert; Hudson, Laurie; Mackenzie, Debra A; Muller, Carolyn Y; Reed, John C; Simons, Peter C; Smagley, Yelena; Strouse, Juan; Surviladze, Zurab; Thompson, Todd; Ursu, Oleg; Waller, Anna; Wandinger-Ness, Angela; Winter, Stuart S; Wu, Yang; Young, Susan M; Larson, Richard S; Willman, Cheryl; Sklar, Larry A

    2011-01-01

    Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the "valley of death" by bridging basic to clinical sciences. PMID:22368688

  10. Drug Repurposing from an Academic Perspective

    PubMed Central

    Oprea, Tudor I.; Bauman, Julie E.; Bologa, Cristian G.; Buranda, Tione; Chigaev, Alexandre; Edwards, Bruce S.; Jarvik, Jonathan W.; Gresham, Hattie D.; Haynes, Mark K.; Hjelle, Brian; Hromas, Robert; Hudson, Laurie; Mackenzie, Debra A.; Muller, Carolyn Y.; Reed, John C.; Simons, Peter C.; Smagley, Yelena; Strouse, Juan; Surviladze, Zurab; Thompson, Todd; Ursu, Oleg; Waller, Anna; Wandinger-Ness, Angela; Winter, Stuart S.; Wu, Yang; Young, Susan M.; Larson, Richard S.; Willman, Cheryl; Sklar, Larry A.

    2011-01-01

    Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the “valley of death” by bridging basic to clinical sciences. PMID:22368688

  11. Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery

    PubMed Central

    Ekins, Sean; Freundlich, Joel S.; Choi, Inhee; Sarker, Malabika; Talcott, Carolyn

    2010-01-01

    We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage this data in order to move from a hit to a lead to a clinical candidate and potentially a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are herein reviewed. We suggest these computational approaches should be more optimally integrated in a workflow with experimental approaches to accelerate TB drug discovery. PMID:21129975

  12. Panacea, a semantic-enabled drug recommendations discovery framework

    PubMed Central

    2014-01-01

    Background Personalized drug prescription can be benefited from the use of intelligent information management and sharing. International standard classifications and terminologies have been developed in order to provide unique and unambiguous information representation. Such standards can be used as the basis of automated decision support systems for providing drug-drug and drug-disease interaction discovery. Additionally, Semantic Web technologies have been proposed in earlier works, in order to support such systems. Results The paper presents Panacea, a semantic framework capable of offering drug-drug and drug-diseases interaction discovery. For enabling this kind of service, medical information and terminology had to be translated to ontological terms and be appropriately coupled with medical knowledge of the field. International standard classifications and terminologies, provide the backbone of the common representation of medical data while the medical knowledge of drug interactions is represented by a rule base which makes use of the aforementioned standards. Representation is based on a lightweight ontology. A layered reasoning approach is implemented where at the first layer ontological inference is used in order to discover underlying knowledge, while at the second layer a two-step rule selection strategy is followed resulting in a computationally efficient reasoning approach. Details of the system architecture are presented while also giving an outline of the difficulties that had to be overcome. Conclusions Panacea is evaluated both in terms of quality of recommendations against real clinical data and performance. The quality recommendation gave useful insights regarding requirements for real world deployment and revealed several parameters that affected the recommendation results. Performance-wise, Panacea is compared to a previous published work by the authors, a service for drug recommendations named GalenOWL, and presents their differences in

  13. Computationally driven drug discovery meeting-3 - Verona (Italy): 4 - 6th of March 2014.

    PubMed

    Costantino, Gabriele

    2014-12-01

    The following article reports on the results and the outcome of a meeting organised at the Aptuit Auditorium in Verona (Italy), which highlighted the current applications of state-of-the-art computational science to drug design in Italy. The meeting, which had > 100 people in attendance, consisted of over 40 presentations and included keynote lectures given by world-renowned speakers. The topics included in the meeting are areas related to ligand and structure-based ligand design and library design and screening; it also provided discussion pertaining to chemometrics. The meeting also stressed the importance of public-private collaboration and reviewed the different approaches to computationally driven drug discovery taken within academia and industry. The meeting helped define the current position of state-of-the-art computational drug discovery in Italy, pointing out criticalities and assets. This kind of focused meeting is important in the sense that it lends the opportunity of a restricted yet representative community of fellow professionals to deeply discuss the current methodological approaches and provide future perspectives for computationally driven drug discovery. PMID:25090581

  14. Emerging Concepts and Approaches for Chemokine-Receptor Drug Discovery

    PubMed Central

    O’Hayre, Morgan; Salanga, Catherina L.; Handel, Tracy M.; Hamel, Damon J.

    2010-01-01

    Importance of the field Chemokine receptors are G protein-coupled receptors (GPCRs) most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets. Areas covered in this review Allostery, oligomerization, and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors. What the reader will gain Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery. Take home message Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches. PMID:21132095

  15. Understanding drug preferences, different perspectives

    PubMed Central

    Mol, Peter G M; Arnardottir, Arna H; Straus, Sabine M J; de Graeff, Pieter A; Haaijer-Ruskamp, Flora M; Quik, Elise H; Krabbe, Paul F M; Denig, Petra

    2015-01-01

    Aims To compare the values regulators attach to different drug effects of oral antidiabetic drugs with those of doctors and patients. Methods We administered a ‘discrete choice’ survey to regulators, doctors and patients with type 2 diabetes in The Netherlands. Eighteen choice sets comparing two hypothetical oral antidiabetic drugs were constructed with varying drug effects on glycated haemoglobin, cardiovascular risk, bodyweight, duration of gastrointestinal complaints, frequency of hypoglycaemia and risk of bladder cancer. Responders were asked each time which drug they preferred. Results Fifty-two regulators, 175 doctors and 226 patients returned the survey. Multinomial conditional logit analyses showed that cardiovascular risk reduction was valued by regulators positively (odds ratio 1.98, 95% confidence interval 1.11–3.53), whereas drug choices were negatively affected by persistent gastrointestinal problems (odds ratio 0.24, 95% confidence interval 0.14–0.41) and cardiovascular risk increase (odds ratio 0.49, 95% confidence interval 0.27–0.87). Doctors and patients valued these effects in a similar manner to regulators. The values that doctors attached to large changes in glycated haemoglobin and that both doctors and patients attached to hypoglycaemia and weight gain also reached statistical significance. No group's drug choice was affected by a small absolute change in risk of bladder cancer when presented in the context of other drug effects. When comparing the groups, the value attached by regulators to less frequent hypoglycaemic episodes was significantly smaller than by patients (P = 0.044). Conclusions Regulators may value major benefits and risks of drugs for an individual diabetes patient mostly in the same way as doctors and patients, but differences may exist regarding the value of minor or short-term drug effects. PMID:25469876

  16. Discovery of the Philadelphia chromosome: a personal perspective

    PubMed Central

    Nowell, Peter C.

    2007-01-01

    Almost 50 years ago, David Hungerford and I noticed an abnormally small chromosome in cells from patients with chronic myelogenous leukemia (CML). This article is a personal perspective of the events leading to the discovery of this chromosome, which became known as the Philadelphia chromosome. As technology advanced over subsequent decades, the translocation resulting in the Philadelphia chromosome has been identified, its role in the development of CML has been confirmed, and a therapy directed against the abnormal protein it produces has shown promising results in the treatment of patients with CML. PMID:17671636

  17. Use of Benford's law in drug discovery data.

    PubMed

    Orita, Masaya; Moritomo, Ayako; Niimi, Tatsuya; Ohno, Kazuki

    2010-05-01

    Benford's law states that the distribution of the first digit of many data sets is not uniform. The first digit of any random number will be 1 almost 30% of the time, and larger digits occur as the first digit with lower and lower frequency, to the point where 9 occurs as a first digit only 5% of the time. Here, we demonstrate that several data sets in the field of drug discovery follow Benford's distribution, whereas 'doctored' data do not. Our findings indicate the applicability of Benford's law in assessing data quality in the field of drug discovery. We also propose a useful index of evaluating data quality based on Benford's law. PMID:20298800

  18. Biomimetic tissues on a chip for drug discovery

    PubMed Central

    Ghaemmaghami, Amir M.; Hancock, Matthew J.; Harrington, Helen; Kaji, Hirokazu; Khademhosseini, Ali

    2011-01-01

    Teaser Recent advances in tissue engineering have enabled the development of microscale biomimetic ‘organ on a chip’ tissue models which have the potential to make an important impact on the various stages of drug discovery and toxicity testing. Developing biologically relevant models of human tissues and organs is an important enabling step for disease modeling and drug discovery. Recent advances in tissue engineering, biomaterials and microfluidics have led to the development of microscale functional units of such models also referred to as ‘organs on a chip’. In this review, we provide an overview of key enabling technologies and highlight the wealth of recent work regarding on-chip tissue models. In addition, we discuss the current challenges and future directions of organ-on-chip development. PMID:22094245

  19. A Historical Overview of Natural Products in Drug Discovery

    PubMed Central

    Dias, Daniel A.; Urban, Sylvia; Roessner, Ute

    2012-01-01

    Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed. PMID:24957513

  20. Pharmacophore-based discovery of ligands for drug transporters

    PubMed Central

    Chang, Cheng; Ekins, Sean; Bahadduri, Praveen; Swaan, Peter W.

    2006-01-01

    The ability to identify ligands for drug transporters is an important step in drug discovery and development. It can both improve accurate profiling of lead pharmacokinetic properties and assist in the discovery of new chemical entities targeting transporters. In silico approaches, especially pharmacophore-based database screening methods have great potential in improving the throughput of current transporter ligand identification assays, leading to a higher hit rate by focusing in vitro testing to the most promising hits. In this review, the potential of different in silico methods in transporter ligand identification studies are compared and summarized with an emphasis on pharmacophore modeling. Various implementations of pharmacophore model generation, database compilation and flexible screening algorithms are also introduced. Recent successful utilization of database searching with pharmacophores to identify novel ligands for the pharmaceutically significant transporters hPepT1, P-gp, BCRP, MRP1 and DAT are reviewed and challenges encountered with current approaches are discussed. PMID:17097188

  1. The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

    PubMed Central

    Wright, Peter M.; Seiple, Ian B.; Myers, Andrew G.

    2015-01-01

    The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted. PMID:24990531

  2. Mobile apps for chemistry in the world of drug discovery.

    PubMed

    Williams, Antony J; Ekins, Sean; Clark, Alex M; Jack, J James; Apodaca, Richard L

    2011-11-01

    Mobile hardware and software technology continues to evolve very rapidly and presents drug discovery scientists with new platforms for accessing data and performing data analysis. Smartphones and tablet computers can now be used to perform many of the operations previously addressed by laptops or desktop computers. Although the smaller screen sizes and requirements for touch-screen manipulation can present user-interface design challenges, especially with chemistry-related applications, these limitations are driving innovative solutions. In this early review of the topic, we collectively present our diverse experiences as software developer, chemistry database expert and naïve user, in terms of what mobile platforms could provide to the drug discovery chemist in the way of applications in the future as this disruptive technology takes off. PMID:21924376

  3. The evolving role of chemical synthesis in antibacterial drug discovery.

    PubMed

    Wright, Peter M; Seiple, Ian B; Myers, Andrew G

    2014-08-18

    The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted. PMID:24990531

  4. Alchemical free energy methods for drug discovery: Progress and challenges

    PubMed Central

    Chodera, John D.; Mobley, David L.; Shirts, Michael R.; Dixon, Richard W.; Branson, Kim; Pande, Vijay S.

    2011-01-01

    Improved rational drug design methods are needed to lower the cost and increase the success rate of drug discovery and development. Alchemical binding free energy calculations, one potential tool for rational design, have progressed rapidly over the last decade, but still fall short of providing robust tools for pharmaceutical engineering. Recent studies, especially on model receptor systems, have clarified many of the challenges that must be overcome for robust predictions of binding affnity to be useful in rational design. In this review, inspired by a recent joint academic/industry meeting organized by the authors, we discuss these challenges and suggest a number of promising approaches for overcoming them. PMID:21349700

  5. Recent Advances in Drug Discovery from South African Marine Invertebrates.

    PubMed

    Davies-Coleman, Michael T; Veale, Clinton G L

    2015-10-01

    Recent developments in marine drug discovery from three South African marine invertebrates, the tube worm Cephalodiscus gilchristi, the ascidian Lissoclinum sp. and the sponge Topsentia pachastrelloides, are presented. Recent reports of the bioactivity and synthesis of the anti-cancer secondary metabolites cephalostatin and mandelalides (from C. gilchristi and Lissoclinum sp., respectively) and various analogues are presented. The threat of drug-resistant pathogens, e.g., methicillin-resistant Staphylococcus aureus (MRSA), is assuming greater global significance, and medicinal chemistry strategies to exploit the potent MRSA PK inhibition, first revealed by two marine secondary metabolites, cis-3,4-dihydrohamacanthin B and bromodeoxytopsentin from T. pachastrelloides, are compared. PMID:26473891

  6. Natural Products as a Foundation for Drug Discovery

    PubMed Central

    Beutler, John A.

    2009-01-01

    Natural products have contributed to the development of many drugs for diverse indications. While most U.S. pharmaceutical companies have reduced or eliminated their in-house natural product groups, new paradigms and new enterprises have evolved to carry on a role for natural products in the pharmaceutical industry. Many of the reasons for the decline in popularity of natural products are being addressed by the development of new techniques for screening and production. This overview aims to inform pharmacologists of current strategies and techniques that make natural products a viable strategic choice for inclusion in drug discovery programs. PMID:20161632

  7. Using Literature-Based Discovery to Explain Adverse Drug Effects.

    PubMed

    Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Burgun, Anita; Žiberna, Lovro; Rindflesch, Thomas C

    2016-08-01

    We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects. PMID:27318993

  8. INTEGRATING COMPUTATIONAL PROTEIN FUNCTION PREDICTION INTO DRUG DISCOVERY INITIATIVES

    PubMed Central

    Grant, Marianne A.

    2014-01-01

    Pharmaceutical researchers must evaluate vast numbers of protein sequences and formulate innovative strategies for identifying valid targets and discovering leads against them as a way of accelerating drug discovery. The ever increasing number and diversity of novel protein sequences identified by genomic sequencing projects and the success of worldwide structural genomics initiatives have spurred great interest and impetus in the development of methods for accurate, computationally empowered protein function prediction and active site identification. Previously, in the absence of direct experimental evidence, homology-based protein function annotation remained the gold-standard for in silico analysis and prediction of protein function. However, with the continued exponential expansion of sequence databases, this approach is not always applicable, as fewer query protein sequences demonstrate significant homology to protein gene products of known function. As a result, several non-homology based methods for protein function prediction that are based on sequence features, structure, evolution, biochemical and genetic knowledge have emerged. Herein, we review current bioinformatic programs and approaches for protein function prediction/annotation and discuss their integration into drug discovery initiatives. The development of such methods to annotate protein functional sites and their application to large protein functional families is crucial to successfully utilizing the vast amounts of genomic sequence information available to drug discovery and development processes. PMID:25530654

  9. ACFIS: a web server for fragment-based drug discovery

    PubMed Central

    Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

    2016-01-01

    In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown ‘chemical space’ to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for ‘chemical space’, which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. PMID:27150808

  10. ACFIS: a web server for fragment-based drug discovery.

    PubMed

    Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

    2016-07-01

    In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown 'chemical space' to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for 'chemical space', which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. PMID:27150808

  11. Structure-based virtual screening for drug discovery: a problem-centric review.

    PubMed

    Cheng, Tiejun; Li, Qingliang; Zhou, Zhigang; Wang, Yanli; Bryant, Stephen H

    2012-03-01

    Structure-based virtual screening (SBVS) has been widely applied in early-stage drug discovery. From a problem-centric perspective, we reviewed the recent advances and applications in SBVS with a special focus on docking-based virtual screening. We emphasized the researchers' practical efforts in real projects by understanding the ligand-target binding interactions as a premise. We also highlighted the recent progress in developing target-biased scoring functions by optimizing current generic scoring functions toward certain target classes, as well as in developing novel ones by means of machine learning techniques. PMID:22281989

  12. [Applications of the Fragment Molecular Orbital Method in Drug Discovery].

    PubMed

    Ishikawa, Takeshi

    2016-01-01

      Recently, ab initio quantum mechanical calculations have been applied to large molecules, including biomolecular systems. The fragment molecular orbital (FMO) method is one of the most efficient approaches for the quantum mechanical investigation of such molecules. In the FMO method, dividing a target molecule into small fragments reduces computational effort. The clear definition of inter-fragment interaction energy (IFIE) as an expression of total energy is another valuable feature of the FMO method because it provides the ability to analyze interactions in biomolecules. Thus, the FMO method is expected to be useful for drug discovery. This study demonstrates applications of the FMO method related to drug discovery. First, IFIE, according to FMO calculations, was used in the optimization of drug candidates for the development of anti-prion compounds. The second example involved interaction analysis of the human immunodeficiency virus type 1 (HIV-1) protease and a drug compound that used a novel analytical method for dispersion interaction, i.e., fragment interaction analysis based on LMP2 (FILM). PMID:26725679

  13. 50 years of hurdles and hope in anxiolytic drug discovery

    PubMed Central

    Griebel, Guy; Holmes, Andrew

    2014-01-01

    Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. PMID:23989795

  14. Modern advances in heterocyclic chemistry in drug discovery.

    PubMed

    Taylor, Alexandria P; Robinson, Ralph P; Fobian, Yvette M; Blakemore, David C; Jones, Lyn H; Fadeyi, Olugbeminiyi

    2016-07-12

    New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted. PMID:27282396

  15. Structural Genomics and Drug Discovery for Infectious Diseases

    SciTech Connect

    Anderson, W.F.

    2010-09-03

    The application of structural genomics methods and approaches to proteins from organisms causing infectious diseases is making available the three dimensional structures of many proteins that are potential drug targets and laying the groundwork for structure aided drug discovery efforts. There are a number of structural genomics projects with a focus on pathogens that have been initiated worldwide. The Center for Structural Genomics of Infectious Diseases (CSGID) was recently established to apply state-of-the-art high throughput structural biology technologies to the characterization of proteins from the National Institute for Allergy and Infectious Diseases (NIAID) category A-C pathogens and organisms causing emerging, or re-emerging infectious diseases. The target selection process emphasizes potential biomedical benefits. Selected proteins include known drug targets and their homologs, essential enzymes, virulence factors and vaccine candidates. The Center also provides a structure determination service for the infectious disease scientific community. The ultimate goal is to generate a library of structures that are available to the scientific community and can serve as a starting point for further research and structure aided drug discovery for infectious diseases. To achieve this goal, the CSGID will determine protein crystal structures of 400 proteins and protein-ligand complexes using proven, rapid, highly integrated, and cost-effective methods for such determination, primarily by X-ray crystallography. High throughput crystallographic structure determination is greatly aided by frequent, convenient access to high-performance beamlines at third-generation synchrotron X-ray sources.

  16. Machine-Learning Techniques Applied to Antibacterial Drug Discovery

    PubMed Central

    Durrant, Jacob D.; Amaro, Rommie E.

    2014-01-01

    The emergence of drug-resistant bacteria threatens to catapult humanity back to the pre-antibiotic era. Even now, multi-drug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the resulting vacuum. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics in an academic setting, leading to improved hit rates and faster transitions to pre-clinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642

  17. A new era for chagas disease drug discovery?

    PubMed

    Keenan, Martine; Chaplin, Jason H

    2015-01-01

    Recent clinical trials investigating treatment of chronic indeterminate Chagas disease with two re-purposed azole anti-fungal drugs, posaconazole and ravuconazole, revealed their inferiority to the current standard-of-care benznidazole and highlighted the inadequacy of the existing pre-clinical testing paradigm for this disease. A very limited number of controlled clinical trials for Chagas disease have been conducted to date. The selection of these compounds for clinical evaluation relied heavily on pre-clinical data obtained from in vitro screens and animal studies. This chapter reviews the evolution of CYP51 as a target for Trypanosoma cruzi growth inhibition and also explores the impact of clinical trial data on contemporary Chagas disease drug discovery. Advances in pre-clinical profiling assays, the current compound landscape and progress towards the identification of new drug targets to re-invigorate research are reviewed. PMID:25727705

  18. Historical Perspective: What Constitutes Discovery (of a New Virus)?

    PubMed

    Murphy, F A

    2016-01-01

    A historic review of the discovery of new viruses leads to reminders of traditions that have evolved over 118 years. One such tradition gives credit for the discovery of a virus to the investigator(s) who not only carried out the seminal experiments but also correctly interpreted the findings (within the technological context of the day). Early on, ultrafiltration played a unique role in "proving" that an infectious agent was a virus, as did a failure to find any microscopically visible agent, failure to show replication of the agent in the absence of viable cells, thermolability of the agent, and demonstration of a specific immune response to the agent so as to rule out duplicates and close variants. More difficult was "proving" that the new virus was the etiologic agent of the disease ("proof of causation")-for good reasons this matter has been revisited several times over the years as technologies and perspectives have changed. One tradition is that the discoverers get to name their discovery, their new virus (unless some grievous convention has been broken)-the stability of these virus names has been a way to honor the discoverer(s) over the long term. Several vignettes have been chosen to illustrate several difficulties in holding to the traditions (vignettes chosen include vaccinia and variola viruses, yellow fever virus, and influenza viruses. Crimean-Congo hemorrhagic fever virus, Murray Valley encephalitis virus, human immunodeficiency virus 1, Sin Nombre virus, and Ebola virus). Each suggests lessons for the future. One way to assure that discoveries are forever linked with discoverers would be a permanent archive in one of the universal virus databases that have been constructed for other purposes. However, no current database seems ideal-perhaps members of the global community of virologists will have an ideal solution. PMID:27112283

  19. Fragment-based drug discovery and molecular docking in drug design.

    PubMed

    Wang, Tao; Wu, Mian-Bin; Chen, Zheng-Jie; Chen, Hua; Lin, Jian-Ping; Yang, Li-Rong

    2015-01-01

    Fragment-based drug discovery (FBDD) has caused a revolution in the process of drug discovery and design, with many FBDD leads being developed into clinical trials or approved in the past few years. Compared with traditional high-throughput screening, it displays obvious advantages such as efficiently covering chemical space, achieving higher hit rates, and so forth. In this review, we focus on the most recent developments of FBDD for improving drug discovery, illustrating the process and the importance of FBDD. In particular, the computational strategies applied in the process of FBDD and molecular-docking programs are highlighted elaborately. In most cases, docking is used for predicting the ligand-receptor interaction modes and hit identification by structurebased virtual screening. The successful cases of typical significance and the hits identified most recently are discussed. PMID:25420726

  20. In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery

    PubMed Central

    Darvesh, Altaf S.; Carroll, Richard T.; Geldenhuys, Werner J.; Gudelsky, Gary A.; Klein, Jochen; Meshul, Charles K.; Van der Schyf, Cornelis J.

    2010-01-01

    Introduction Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. Areas covered In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. Expert opinion In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases

  1. Drug Discovery of Host CLK1 Inhibitors for Influenza Treatment.

    PubMed

    Zu, Mian; Li, Chao; Fang, Jian-Song; Lian, Wen-Wen; Liu, Ai-Lin; Zheng, Li-Shu; Du, Guan-Hua

    2015-01-01

    The rapid evolution of influenza virus makes antiviral drugs less effective, which is considered to be a major bottleneck in antiviral therapy. The key proteins in the host cells, which are related with the replication cycle of influenza virus, are regarded as potential drug targets due to their distinct advantage of lack of evolution and drug resistance. Cdc2-like kinase 1 (CLK1) in the host cells is responsible for alternative splicing of the M2 gene of influenza virus during influenza infection and replication. In this study, we carried out baculovirus-mediated expression and purification of CLK1 and established a reliable screening assay for CLK1 inhibitors. After a virtual screening of CLK1 inhibitors was performed, the activities of the selected compounds were evaluated. Finally, several compounds with strong inhibitory activity against CLK1 were discovered and their in vitro anti-influenza virus activities were validated using a cytopathic effect (CPE) reduction assay. The assay results showed that clypearin, corilagin, and pinosylvine were the most potential anti-influenza virus compounds as CLK1 inhibitors among the compounds tested. These findings will provide important information for new drug design and development in influenza treatment, and CLK1 may be a potent drug target for anti-influenza drug screening and discovery. PMID:26540031

  2. Use of "big data" in drug discovery and clinical trials.

    PubMed

    Taglang, Guillaume; Jackson, David B

    2016-04-01

    Oncology is undergoing a data-driven metamorphosis. Armed with new and ever more efficient molecular and information technologies, we have entered an era where data is helping us spearhead the fight against cancer. This technology driven data explosion, often referred to as "big data", is not only expediting biomedical discovery, but it is also rapidly transforming the practice of oncology into an information science. This evolution is critical, as results to-date have revealed the immense complexity and genetic heterogeneity of patients and their tumors, a sobering reminder of the challenge facing every patient and their oncologist. This can only be addressed through development of clinico-molecular data analytics that provide a deeper understanding of the mechanisms controlling the biological and clinical response to available therapeutic options. Beyond the exciting implications for improved patient care, such advancements in predictive and evidence-based analytics stand to profoundly affect the processes of cancer drug discovery and associated clinical trials. PMID:27016224

  3. Perspectives on transdermal ultrasound mediated drug delivery

    PubMed Central

    Smith, Nadine Barrie

    2007-01-01

    The use of needles for multiple injection of drugs, such as insulin for diabetes, can be painful. As a result, prescribed drug noncompliance can result in severe medical complications. Several noninvasive methods exist for transdermal drug delivery. These include chemical mediation using liposomes and chemical enhancers or physical mechanisms such as microneedles, iontophoresis, electroporation, and ultrasound. Ultrasound enhanced transdermal drug delivery offers advantages over traditional drug delivery methods which are often invasive and painful. A broad review of the transdermal ultrasound drug delivery literature has shown that this technology offers promising potential for noninvasive drug administration. From a clinical perspective, few drugs, proteins or peptides have been successfully administered transdermally because of the low skin permeability to these relatively large molecules, although much work is underway to resolve this problem. The proposed mechanism of ultrasound has been suggested to be the result of cavitation, which is discussed along with the bioeffects from therapeutic ultrasound. For low frequencies, potential transducers which can be used for drug delivery are discussed, along with cautions regarding ultrasound safety versus efficacy. PMID:18203426

  4. Stimulated Raman scattering microscopy: an emerging tool for drug discovery.

    PubMed

    Tipping, W J; Lee, M; Serrels, A; Brunton, V G; Hulme, A N

    2016-04-21

    Optical microscopy techniques have emerged as a cornerstone of biomedical research, capable of probing the cellular functions of a vast range of substrates, whilst being minimally invasive to the cells or tissues of interest. Incorporating biological imaging into the early stages of the drug discovery process can provide invaluable information about drug activity within complex disease models. Spontaneous Raman spectroscopy has been widely used as a platform for the study of cells and their components based on chemical composition; but slow acquisition rates, poor resolution and a lack of sensitivity have hampered further development. A new generation of stimulated Raman techniques is emerging which allows the imaging of cells, tissues and organisms at faster acquisition speeds, and with greater resolution and sensitivity than previously possible. This review focuses on the development of stimulated Raman scattering (SRS), and covers the use of bioorthogonal tags to enhance sample detection, and recent applications of both spontaneous Raman and SRS as novel imaging platforms to facilitate the drug discovery process. PMID:26839248

  5. Stimulated Raman scattering microscopy: an emerging tool for drug discovery

    PubMed Central

    Tipping, W. J.; Lee, M.; Serrels, A.; Brunton, V. G.

    2016-01-01

    Optical microscopy techniques have emerged as a cornerstone of biomedical research, capable of probing the cellular functions of a vast range of substrates, whilst being minimally invasive to the cells or tissues of interest. Incorporating biological imaging into the early stages of the drug discovery process can provide invaluable information about drug activity within complex disease models. Spontaneous Raman spectroscopy has been widely used as a platform for the study of cells and their components based on chemical composition; but slow acquisition rates, poor resolution and a lack of sensitivity have hampered further development. A new generation of stimulated Raman techniques is emerging which allows the imaging of cells, tissues and organisms at faster acquisition speeds, and with greater resolution and sensitivity than previously possible. This review focuses on the development of stimulated Raman scattering (SRS), and covers the use of bioorthogonal tags to enhance sample detection, and recent applications of both spontaneous Raman and SRS as novel imaging platforms to facilitate the drug discovery process. PMID:26839248

  6. Chemical informatics and the drug discovery knowledge pyramid.

    PubMed

    Lushington, Gerald H; Dong, Yinghua; Theertham, Bhargav

    2013-12-01

    The magnitude of the challenges in preclinical drug discovery is evident in the large amount of capital invested in such efforts in pursuit of a small static number of eventually successful marketable therapeutics. An explosion in the availability of potentially drug-like compounds and chemical biology data on these molecules can provide us with the means to improve the eventual success rates for compounds being considered at the preclinical level, but only if the community is able to access available information in an efficient and meaningful way. Thus, chemical database resources are critical to any serious drug discovery effort. This paper explores the basic principles underlying the development and implementation of chemical databases, and examines key issues of how molecular information may be encoded within these databases so as to enhance the likelihood that users will be able to extract meaningful information from data queries. In addition to a broad survey of conventional data representation and query strategies, key enabling technologies such as new context-sensitive chemical similarity measures and chemical cartridges are examined, with recommendations on how such resources may be integrated into a practical database environment. PMID:23782037

  7. Computer-Aided Drug Discovery and Design Targeting Ion Channels.

    PubMed

    Zhang, Qiansen; Gao, Zhaobing; Yang, Huaiyu

    2016-01-01

    Ion channels are widely expressed in living cells and play critical roles in various cellular biological functions. Dysfunctional ion channels can cause a variety of diseases, making ion channels attractive targets for drug discovery. Computational approaches, such as molecular docking and molecular dynamic simulations, provide economic and efficient tools for finding modulators of ion channels and for elucidating the action mechanisms of small molecules. In this review, we focus primarily on four types of ion channels (voltage-gated, ligand-gated, acid-sensing, and virus matrix 2 ion channels). The current advancements in computer-aided drug discovery and design targeting ion channels are summarized. First, ligand-based studies for drug design are briefly outlined. Then, we focus on the structurebased studies targeting pore domains, endogenous binding sites and allosteric sites of ion channels. Moreover, we also review the contribution of computational methods to the field of ligand binding and unbinding pathways of ion channels. Finally, we propose future developments for the field. PMID:26975507

  8. Advanced Cell Culture Techniques for Cancer Drug Discovery

    PubMed Central

    Lovitt, Carrie J.; Shelper, Todd B.; Avery, Vicky M.

    2014-01-01

    Human cancer cell lines are an integral part of drug discovery practices. However, modeling the complexity of cancer utilizing these cell lines on standard plastic substrata, does not accurately represent the tumor microenvironment. Research into developing advanced tumor cell culture models in a three-dimensional (3D) architecture that more prescisely characterizes the disease state have been undertaken by a number of laboratories around the world. These 3D cell culture models are particularly beneficial for investigating mechanistic processes and drug resistance in tumor cells. In addition, a range of molecular mechanisms deconstructed by studying cancer cells in 3D models suggest that tumor cells cultured in two-dimensional monolayer conditions do not respond to cancer therapeutics/compounds in a similar manner. Recent studies have demonstrated the potential of utilizing 3D cell culture models in drug discovery programs; however, it is evident that further research is required for the development of more complex models that incorporate the majority of the cellular and physical properties of a tumor. PMID:24887773

  9. Genetics of rheumatoid arthritis contributes to biology and drug discovery.

    PubMed

    Okada, Yukinori; Wu, Di; Trynka, Gosia; Raj, Towfique; Terao, Chikashi; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Suzuki, Akari; Yoshida, Shinji; Graham, Robert R; Manoharan, Arun; Ortmann, Ward; Bhangale, Tushar; Denny, Joshua C; Carroll, Robert J; Eyler, Anne E; Greenberg, Jeffrey D; Kremer, Joel M; Pappas, Dimitrios A; Jiang, Lei; Yin, Jian; Ye, Lingying; Su, Ding-Feng; Yang, Jian; Xie, Gang; Keystone, Ed; Westra, Harm-Jan; Esko, Tõnu; Metspalu, Andres; Zhou, Xuezhong; Gupta, Namrata; Mirel, Daniel; Stahl, Eli A; Diogo, Dorothée; Cui, Jing; Liao, Katherine; Guo, Michael H; Myouzen, Keiko; Kawaguchi, Takahisa; Coenen, Marieke J H; van Riel, Piet L C M; van de Laar, Mart A F J; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Bridges, S Louis; Zhernakova, Alexandra; Toes, Rene E M; Tak, Paul P; Miceli-Richard, Corinne; Bang, So-Young; Lee, Hye-Soon; Martin, Javier; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Rantapää-Dahlqvist, Solbritt; Arlestig, Lisbeth; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Eyre, Steve; Bowes, John; Barton, Anne; de Vries, Niek; Moreland, Larry W; Criswell, Lindsey A; Karlson, Elizabeth W; Taniguchi, Atsuo; Yamada, Ryo; Kubo, Michiaki; Liu, Jun S; Bae, Sang-Cheol; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Gregersen, Peter K; Raychaudhuri, Soumya; Stranger, Barbara E; De Jager, Philip L; Franke, Lude; Visscher, Peter M; Brown, Matthew A; Yamanaka, Hisashi; Mimori, Tsuneyo; Takahashi, Atsushi; Xu, Huji; Behrens, Timothy W; Siminovitch, Katherine A; Momohara, Shigeki; Matsuda, Fumihiko; Yamamoto, Kazuhiko; Plenge, Robert M

    2014-02-20

    A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery. PMID:24390342

  10. Chemical Informatics and the Drug Discovery Knowledge Pyramid

    PubMed Central

    Lushington, Gerald H.; Dong, Yinghua; Theertham, Bhargav

    2012-01-01

    The magnitude of the challenges in preclinical drug discovery is evident in the large amount of capital invested in such efforts in pursuit of a small static number of eventually successful marketable therapeutics. An explosion in the availability of potentially drug-like compounds and chemical biology data on these molecules can provide us with the means to improve the eventual success rates for compounds being considered at the preclinical level, but only if the community is able to access available information in an efficient and meaningful way. Thus, chemical database resources are critical to any serious drug discovery effort. This paper explores the basic principles underlying the development and implementation of chemical databases, and examines key issues of how molecular information may be encoded within these databases so as to enhance the likelihood that users will be able to extract meaningful information from data queries. In addition to a broad survey of conventional data representation and query strategies, key enabling technologies such as new context-sensitive chemical similarity measures and chemical cartridges are examined, with recommendations on how such resources may be integrated into a practical database environment. PMID:23782037

  11. Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery.

    PubMed

    Sangshetti, Jaiprakash N; Khan, Firoz A Kalam; Shinde, Devanand B

    2015-01-01

    Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors. PMID:25174923

  12. How chemoproteomics can enable drug discovery and development

    PubMed Central

    Moellering, Raymond E.; Cravatt, Benjamin F.

    2012-01-01

    Creating first-in-class medications to treat human disease is an extremely challenging endeavor. While genome sequencing and genetics are making direct connections between mutations and human disorders at an unprecedented rate, matching molecular target(s) with a suitable therapeutic indication must ultimately be achieved by pharmacology. Here, we will discuss how the integration of chemical proteomic platforms, such as activity-based protein profiling, into the earliest stages of the drug discovery process has the potential to greatly expand the scope of proteins that can be pharmacologically evaluated in living systems, and, through doing so, promote the identification and prioritization of new therapeutic targets. PMID:22284350

  13. Ca2+ mobilization assays in GPCR drug discovery.

    PubMed

    Woszczek, Grzegorz; Fuerst, Elisabeth

    2015-01-01

    Intracellular calcium mobilization can be measured using several methods varying in indicator dyes and devices used. In this chapter, we describe the fluorescence-based method (FLIPR Calcium 4 Assay) developed by Molecular Devices for a FlexStation and routinely used in our laboratory for detecting intracellular calcium changes. The assay is designed to study calcium mobilization induced by majority of GPCRs and calcium channels and allows for simultaneous concentration-dependent analysis of several receptor agonists and antagonists, useful in receptor characterization and drug discovery projects. PMID:25563178

  14. The case for open-source software in drug discovery.

    PubMed

    DeLano, Warren L

    2005-02-01

    Widespread adoption of open-source software for network infrastructure, web servers, code development, and operating systems leads one to ask how far it can go. Will "open source" spread broadly, or will it be restricted to niches frequented by hopeful hobbyists and midnight hackers? Here we identify reasons for the success of open-source software and predict how consumers in drug discovery will benefit from new open-source products that address their needs with increased flexibility and in ways complementary to proprietary options. PMID:15708536

  15. Focusing on shared subpockets - new developments in fragment based drug discovery

    PubMed Central

    Abdelraheem, Eman M. M.; Camacho, Carlos; Dömling, Alexander

    2016-01-01

    Introduction Protein–protein interactions (PPIs) are important targets for understanding fundamental biology and for the development of therapeutic agents. Based on different physicochemical properties, numerous pieces of software (e.g PocketQuery, Anchor and FTMap) have been reported to find pockets on protein surfaces and have applications in facilitating the design and discovery of small molecular weight compounds which bind to these pockets. Areas covered The authors discuss a pocket-centric method of analyzing protein-protein interaction interfaces, which prioritize their pockets for small molecule drug discovery and the importance of multicomponent reaction (MCR) chemistry as starting points for undruggable targets. The authors also provide their perspectives on the field Expert opinion Only the tight interplay of efficient computational methods capable of screening a large chemical space and fast synthetic chemistry will lead to progress in the rational design of PPI antagonists in the future. Early drug discovery platforms will also benefit from efficient rapid feedback loops from early clinical research back to molecular design and the medicinal chemistry bench. PMID:26296101

  16. Chemistry challenges in lead optimization: silicon isosteres in drug discovery.

    PubMed

    Showell, Graham A; Mills, John S

    2003-06-15

    During the lead optimization phase of drug discovery projects, the factors contributing to subsequent failure might include poor portfolio decision-making and a sub-optimal intellectual property (IP) position. The pharmaceutical industry has an ongoing need for new, safe medicines with a genuine biomedical benefit, a clean IP position and commercial viability. Inherent drug-like properties and chemical tractability are also essential for the smooth development of such agents. The introduction of bioisosteres, to improve the properties of a molecule and obtain new classes of compounds without prior art in the patent literature, is a key strategy used by medicinal chemists during the lead optimization process. Sila-substitution (C/Si exchange) of existing drugs is an approach to search for new drug-like candidates that have beneficial biological properties and a clear IP position. Some of the fundamental differences between carbon and silicon can lead to marked alterations in the physicochemical and biological properties of the silicon-containing analogues and the resulting benefits can be exploited in the drug design process. PMID:12821303

  17. Accelerating drug discovery via organs-on-chips

    PubMed Central

    Chan, Chung Yu; Huang, Po-Hsun; Guo, Feng; Ding, Xiaoyun; Kapur, Vivek; Mai, John D.

    2014-01-01

    Considerable advances have been made in the development of micro-physiological systems that seek to faithfully replicate the complexity and functionality of animal and human physiology in research laboratories. Sometimes referred to as “organs-on-chips”, these systems provide key insights into physiological or pathological processes associated with health maintenance and disease control, and serve as powerful platforms for new drug development and toxicity screening. In this Focus article, we review the state-of-the-art designs and examples for developing multiple “organs-on-chips”, and discuss the potential of this emerging technology to enhance our understanding of human physiology, and to transform and accelerate the drug discovery and pre-clinical testing process. This Focus article highlights some of the recent technological advances in this field, along with the challenges that must be addressed for these technologies to fully realize their potential. PMID:24193241

  18. The Zebrafish as a Tool to Cancer Drug Discovery

    PubMed Central

    Huiting, LN; Laroche, FJF; Feng, H

    2015-01-01

    The ability of zebrafish to faithfully recapitulate a variety of human cancers provides a unique in vivo system for drug identification and validation. Zebrafish models of human cancer generated through methodologies such as transgenesis, gene inactivation, transplantation, and carcinogenic induction have proven similar to their human counterparts both molecularly and pathologically. Suppression of cancer-relevant phenotypes provides opportunities to both identify and evaluate efficacious compounds using embryonic and adult zebrafish. After relevant compounds are selected, preclinical evaluation in mammalian models can occur, delivering lead compounds to human trials swiftly and rapidly. The advantages of in vivo imaging, large progeny, and rapid development that the zebrafish provides make it an attractive model to promote novel cancer drug discovery and reduce the hurdles and cost of clinical trials. This review explores the current methodologies to model human cancers in zebrafish, and how these cancer models have aided in formation of novel therapeutic hypotheses. PMID:26835511

  19. Transporter assays and assay ontologies: useful tools for drug discovery.

    PubMed

    Zdrazil, Barbara; Chichester, Christine; Zander Balderud, Linda; Engkvist, Ola; Gaulton, Anna; Overington, John P

    2014-06-01

    Transport proteins represent an eminent class of drug targets and ADMET (absorption, distribution, metabolism, excretion, toxicity) associated genes. There exists a large number of distinct activity assays for transport proteins, depending on not only the measurement needed (e.g. transport activity, strength of ligand–protein interaction), but also due to heterogeneous assay setups used by different research groups. Efforts to systematically organize this (divergent) bioassay data have large potential impact in Public-Private partnership and conventional commercial drug discovery. In this short review, we highlight some of the frequently used high-throughput assays for transport proteins, and we discuss emerging assay ontologies and their application to this field. Focusing on human P-glycoprotein (Multidrug resistance protein 1; gene name: ABCB1, MDR1), we exemplify how annotation of bioassay data per target class could improve and add to existing ontologies, and we propose to include an additional layer of metadata supporting data fusion across different bioassays. PMID:25027375

  20. Collaborative virtual organisation and infrastructure for drug discovery.

    PubMed

    Hardy, Barry; Affentranger, Roman

    2013-07-01

    A virtual organisation approach was applied to collaborative drug discovery integrating experimental and computational design approaches. Scientists Against Malaria was formed with the goal of designing novel antimalarial drug candidates. The collaboration of nine founding partners carried out computational and laboratory work that produced significant volumes of data and metadata, the interpretation for the analysis of which, as well as the related decision making, was challenging. During the first phase the partners developed this 'green-field' project from initiation through to target selection and modelling, computational screening, biological materials and assay preparation, culminating in the completion of initial experimental testing. A support infrastructure involving a semantic collaborative laboratory framework, interoperating with a cloud of web services through an ontology describing the virtual and experimental screening data, was designed and tested. PMID:23416145

  1. Application of SBDD to the discovery of new antibacterial drugs.

    PubMed

    Finn, John

    2012-01-01

    The emergence of bacteria that are multiply resistant to commonly used antibiotics has created the medical need for novel classes of antibacterial agents. The unique challenges to the discovery of new antibacterial drugs include the following: spectrum, selectivity, low emergence of new resistance, and high potency. With the emergence of genomic information, dozens of antibacterial targets have been pursued over the last 2 decades often using SBDD. This chapter reviews the application of structure-based drug design approaches on a selected group of antibacterial targets (DHFR, DHNA, PDF, and FabI) where significant progress has been made. We compare and contrast the different approaches and evaluate the results in terms of the biological profiles of the leads produced. Several common themes have emerged from this survey, resulting in a set of recommendations. PMID:22222458

  2. Exploiting plug-and-play electrochemistry for drug discovery.

    PubMed

    Gao, Lixia; Teng, Yong

    2016-04-01

    Electrochemistry has emerged as a powerful analytical technique for chemical analysis of living cells, biologically active molecules and metabolites. Electrochemical biosensor, microfluidics and mass spectrometry are the most frequently used methods for electrochemical detection and monitory, which comprise a collection of extremely useful measurement tools for various fields of biology and medicine. Most recently, electrochemistry has been shown to be coupled with nanotechnology and genetic engineering to generate new enabling technologies, providing rapid, selective, and sensitive detection and diagnosis platforms. The primary focus of this review is to highlight the utility of electrochemical strategies and their conjunction with other approaches for drug metabolism and discovery. Current challenges and possible future developments and applications of electrochemistry in drug studies are also discussed. PMID:27079543

  3. Voltage gated sodium channels as drug discovery targets

    PubMed Central

    Bagal, Sharan K; Marron, Brian E; Owen, Robert M; Storer, R Ian; Swain, Nigel A

    2015-01-01

    Voltage-gated sodium (NaV) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of NaVs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over-excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter. PMID:26646477

  4. Machine-learning techniques applied to antibacterial drug discovery.

    PubMed

    Durrant, Jacob D; Amaro, Rommie E

    2015-01-01

    The emergence of drug-resistant bacteria threatens to revert humanity back to the preantibiotic era. Even now, multidrug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the pipeline. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug-discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics, leading to improved hit rates and faster transitions to preclinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642

  5. Agreement of drug discovery data with Benford's law.

    PubMed

    Orita, Masaya; Hagiwara, Yosuke; Moritomo, Ayako; Tsunoyama, Kazuhisa; Watanabe, Toshihiro; Ohno, Kazuki

    2013-01-01

    The ever-increasing rate of drug discovery data has complicated data analysis and potentially compromised data quality due to factors such as data handling errors. Parallel to this concern is the rise in blatant scientific misconduct. Combined, these problems highlight the importance of developing a method that can be used to systematically assess data quality. Benford's law has been used to discover data manipulation and data fabrication in various fields. In the authors' previous studies, it was demonstrated that the distribution of the corresponding activity and solubility data followed Benford's law distribution. It was also shown that too intense a selection of training data sets of regression model can disrupt Benford's law. Here, the authors present the application of Benford's law to a wider range of drug discovery data such as microarray and sequence data. They also suggest that Benford's law could also be applied to model building and reliability for structure-activity relationship study. Finally, the authors propose a protocol based on Benford's law which will provide researchers with an efficient method for data quality assessment. However, multifaceted quality control such as combinatorial use with data visualization may also be needed to further improve its reliability. PMID:23121309

  6. Selection of oral bioavailability enhancing formulations during drug discovery.

    PubMed

    Zheng, Weijia; Jain, Akash; Papoutsakis, Dimitris; Dannenfelser, Rose-Marie; Panicucci, Riccardo; Garad, Sudhakar

    2012-02-01

    The objective of this paper was to identify oral bioavailability enhancing approaches for a poorly water-soluble research compound during drug discovery stages using minimal amounts of material. LCQ789 is a pBCS (preclinical BCS) Class II compound with extremely low aqueous solubility (<1 µg/mL) and high permeability, therefore, resulting in very low oral bioavailability in preclinical species (rats and dogs). A number of solubility and/or dissolution enhancing approaches including particle size reduction, solid dispersions, lipid-based formulations and co-crystals, were considered in order to improve the compound's oral bioavailability. High-Throughput Screening (HTS) and in silico modeling (GastroPlus™) were utilized to minimize the compound consumption in early discovery stages. In vivo evaluation of selected physical form and formulation strategies was performed in rats and dogs. Amongst the formulation strategies, optimized solid dispersion and lipid-based formulation provided significant improvement in drug dissolution rate and hence, oral bioavailability. In addition, a significant impact of physical form on oral bioavailability of LCQ789 was observed. In conclusion, a thorough understanding of not only the formulation technique but also the physical form of research compounds is critical to ensure physical stability, successful pharmacokinetic (PK) profiling and early developability risk assessment. PMID:21851310

  7. Contribution of Automated Technologies to Ion Channel Drug Discovery.

    PubMed

    Picones, Arturo; Loza-Huerta, Arlet; Segura-Chama, Pedro; Lara-Figueroa, Cesar O

    2016-01-01

    Automated technologies are now resolving the historical relegation that ion channels have endured as targets for the new drug discovery and development global efforts. The richness and adequacy of functional assay methodologies, remarkably fluorescence-based detection of ions fluxes and patch-clamp electrophysiology recording of ionic currents, are now automated and increasingly employed for the analysis of ion channel activity. While the former is currently the most commonly applied, the latter is finally reaching the throughput capacity to be engaged in the primary screening of chemical libraries conformed by hundreds of thousands of compounds. The use of automated instrumentation for the study of ion channel functionality (and dysfunctionality), particularly in the search for novel pharmacological agents with therapeutic purposes, has now reached out beyond the industrial setting, its original natural enclave, and is making its way into a growing number of academic labs and core facilities. The present chapter reviews the increasing contributions accomplished by a variety of different key automated technologies which have revolutionized the strategies to approach the discovery and development of new drugs targeting ion channels. PMID:27038379

  8. Ten years of dengue drug discovery: progress and prospects.

    PubMed

    Lim, Siew Pheng; Wang, Qing-Yin; Noble, Christian G; Chen, Yen-Liang; Dong, Hongping; Zou, Bin; Yokokawa, Fumiaki; Nilar, Shahul; Smith, Paul; Beer, David; Lescar, Julien; Shi, Pei-Yong

    2013-11-01

    To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the Singapore Economic Development Board. One of NITD's missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we review the progress in dengue drug discovery made at NITD as well as the major discoveries made by academia and other companies. Four strategies have been pursued to identify inhibitors of DENV through targeting both viral and host proteins: (i) HTS (high-throughput screening) using virus replication assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along the developmental process from hit finding to clinical candidate, many inhibitors did not advance beyond the stage of hit-to-lead optimization, due to their poor selectivity, physiochemical or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs, NITD-008 and Balapiravir, entered preclinical animal safety study and clinic trial, but both were terminated due to toxicity and lack of potency, respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under clinical trial; its clinical efficacy remains to be determined. The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery. Though challenging, we are optimistic that this continuous, concerted effort will lead to an effective dengue therapy. PMID:24076358

  9. Systems drug discovery: a quantitative, objective approach for safer drug development.

    PubMed

    Bickle, Marc

    2012-09-01

    We are currently witnessing a dramatic change in the pharmaceutical industry as many companies are downscaling their efforts to discover new drug candidates and are instead turning toward collaboration with academic partners. This trend has been dubbed open innovation. The reason for this change of policy stems from the realization that, in spite of massive investments in their drug development programs in the past 30 years, the number of new drugs reaching the market has remained stable over the same period. We review past and present drug discovery strategies and present a novel more holistic approach that we term Systems Drug Discovery. This approach aims at quantifying the physiological state of organ slice cultures using high content imaging and metabolomics. The characterization in a quantitative manner of healthy, diseased, and drug-treated tissues will allow defining a multiparametric space, within which tissues are healthy. This in turn will allow an objective assessment of the impact of candidate drugs on cells. This quantitative approach should help guide the development of new drugs reducing failure rates in clinical phase. PMID:22827715

  10. Androgen receptor: structure, role in prostate cancer and drug discovery

    PubMed Central

    Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

    2015-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

  11. Emerging Computational Methods for the Rational Discovery of Allosteric Drugs.

    PubMed

    Wagner, Jeffrey R; Lee, Christopher T; Durrant, Jacob D; Malmstrom, Robert D; Feher, Victoria A; Amaro, Rommie E

    2016-06-01

    Allosteric drug development holds promise for delivering medicines that are more selective and less toxic than those that target orthosteric sites. To date, the discovery of allosteric binding sites and lead compounds has been mostly serendipitous, achieved through high-throughput screening. Over the past decade, structural data has become more readily available for larger protein systems and more membrane protein classes (e.g., GPCRs and ion channels), which are common allosteric drug targets. In parallel, improved simulation methods now provide better atomistic understanding of the protein dynamics and cooperative motions that are critical to allosteric mechanisms. As a result of these advances, the field of predictive allosteric drug development is now on the cusp of a new era of rational structure-based computational methods. Here, we review algorithms that predict allosteric sites based on sequence data and molecular dynamics simulations, describe tools that assess the druggability of these pockets, and discuss how Markov state models and topology analyses provide insight into the relationship between protein dynamics and allosteric drug binding. In each section, we first provide an overview of the various method classes before describing relevant algorithms and software packages. PMID:27074285

  12. Emerging Computational Methods for the Rational Discovery of Allosteric Drugs

    PubMed Central

    2016-01-01

    Allosteric drug development holds promise for delivering medicines that are more selective and less toxic than those that target orthosteric sites. To date, the discovery of allosteric binding sites and lead compounds has been mostly serendipitous, achieved through high-throughput screening. Over the past decade, structural data has become more readily available for larger protein systems and more membrane protein classes (e.g., GPCRs and ion channels), which are common allosteric drug targets. In parallel, improved simulation methods now provide better atomistic understanding of the protein dynamics and cooperative motions that are critical to allosteric mechanisms. As a result of these advances, the field of predictive allosteric drug development is now on the cusp of a new era of rational structure-based computational methods. Here, we review algorithms that predict allosteric sites based on sequence data and molecular dynamics simulations, describe tools that assess the druggability of these pockets, and discuss how Markov state models and topology analyses provide insight into the relationship between protein dynamics and allosteric drug binding. In each section, we first provide an overview of the various method classes before describing relevant algorithms and software packages. PMID:27074285

  13. Exploring open innovation with a patient focus in drug discovery: an evolving paradigm of patient engagement.

    PubMed

    Allarakhia, Minna

    2015-06-01

    It is suggested in this article that patient engagement should occur further upstream during the drug discovery stage. 'Lead patients', namely those patients who are proactive with respect to their health, possess knowledge of their disease and resulting symptoms. They are also well informed about the conventional as well as non-conventional treatments for disease management; and so can provide a nuanced perspective to drug design. Understanding how patients view the management of their diseases and how they view the use of conventional versus non-conventional interventions is of imperative importance to researchers. Indeed, this can provide insight into how conventional treatments might be designed from the outset to encourage compliance and positive health outcomes. Consequently, a continuum of lead patient engagement is employed that focuses on drug discovery processes ranging from participative, informative to collaborative engagement. This article looks at a variety of open innovation models that are currently employed across this engagement spectrum. It is no longer sufficient for industry stakeholders to consider conventional therapies as the only mechanisms being sought after by patients. Without patient engagement, the industry risks being re-prioritized in terms of its role in the patient journey towards not only recovery of health, but also sustained health and wellness before disease onset. PMID:25872566

  14. Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?

    PubMed

    Smith, Dennis; Schmid, Esther; Jones, Barry

    2002-01-01

    The alignment of drug metabolism and pharmacokinetic departments with drug discovery has not produced a radical improvement in the pharmacokinetic properties of new chemical entities. The reason for this is complex, reflecting in part the difficulty of combining potency, selectivity, water solubility, metabolic stability and membrane permeability into a single molecule. This combination becomes increasingly problematic as the drug targets become more distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads available for aminergic 7-TMs, like the natural agonists, are invariably small molecular weight, water soluble and potent. Even moving to 7-TMs for which the agonist is a peptide invariably produces lead matter that is less drug-like (higher molecular weight and lipophilic). The role of drug metabolism departments, therefore, has been to guide chemistry to obtaining adequate, rather than optimal, pharmacokinetic properties for these 'difficult' drug targets. A consistent belief of many researchers is that a high value is placed on optimal, rather than adequate, pharmacokinetic properties. One measure of value is market sales, and when these are examined no clear pattern emerges. Part of the success of amlodipine in the calcium channel antagonist sector must be due to its excellent pharmacokinetic profile, but the best-selling drugs among the angiotensin antagonists and beta-blockers have a much greater market share than other agents with better pharmacokinetic properties. Clearly, many other factors are important in the successful launch of a medicine, some reflected in the manner the compound is developed and the subsequent structure of the labelling. Overall, therefore the presence of drug metabolism in drug discovery has probably contributed most by allowing 'difficult' drug targets to be prosecuted, rather than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult' target candidates become successful drugs when

  15. Development of an ADME and drug-drug interactions knowledge database for the acceleration of drug discovery and development.

    PubMed

    Petitet, François; Barberan, Olivier; Dubus, Elodie; Ijjaali, Ismail; Donlan, Mary; Ollivier, Sophie; Michel, André

    2006-12-01

    It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE(®) ADME/DDI (drug-drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug-drug interactions. PMID:23495997

  16. Integrated expressional analysis: application to the drug discovery process.

    PubMed

    Ilyin, Sergey E; Horowitz, Daniel; Belkowski, Stanley M; Xin, Hong; Eckardt, Annette J; Darrow, Andrew L; Chen, Cailin; Maley, Derrick; D'Andrea, Michael; Plata-Salamán, Carlos R; Derian, Claudia K

    2005-11-01

    Microarray technology enables high-throughput testing of gene expression to investigate various neuroscience related questions. This in turn creates a demand for scalable methods to confirm microarray results and the opportunity to use this information to discover and test novel pathways and therapeutic applications. Discovery of new central nervous system (CNS) treatments requires a comprehensive understanding of multiple aspects including the biology of a target, the pathophysiology of a disease/disorder, and the selection of successful lead compounds as well as efficient biomarker and drug disposition strategies such as absorption (how a drug is absorbed), distribution (how a drug spreads through an organism), metabolism (chemical conversion of a drug, if any, and into which substances), and elimination (how is a drug eliminated) (ADME). Understanding of the toxicity is also of paramount importance. These approaches, in turn, require novel high-content integrative assay technologies that provide thorough information about changes in cell biology. To increase efficiency of profiling, characterization, and validation, we established a new screening strategy that combines high-content image-based testing on Array Scan (Cellomics) with a confocal system and the multiplexed TaqMan RT-PCR method for quantitative mRNA expression analysis. This approach could serve as an interface between high-throughput microarray testing and specific application of markers discovered in the course of a microarray experiment. Markers could pinpoint activation or inhibition of a molecular pathway related, for instance, to neuronal viability. We demonstrate the successful testing of the same cell population in an image-based translocational assay followed by poly(A) mRNA capture and multiplexed single tube RT-PCR. In addition, Ciphergen ProteinChip analysis can be performed on the supernatant, thus allowing significant complementarity in the data output and interpretation by also

  17. Distributed Drug Discovery: Advancing Chemical Education through Contextualized Combinatorial Solid-Phase Organic Laboratories

    ERIC Educational Resources Information Center

    Scott, William L.; Denton, Ryan E.; Marrs, Kathleen A.; Durrant, Jacob D.; Samaritoni, J. Geno; Abraham, Milata M.; Brown, Stephen P.; Carnahan, Jon M.; Fischer, Lindsey G.; Glos, Courtney E.; Sempsrott, Peter J.; O'Donnell, Martin J.

    2015-01-01

    The Distributed Drug Discovery (D3) program trains students in three drug discovery disciplines (synthesis, computational analysis, and biological screening) while addressing the important challenge of discovering drug leads for neglected diseases. This article focuses on implementation of the synthesis component in the second-semester…

  18. A development perspective on adolescent drug abuse.

    PubMed

    Baumrind, D; Moselle, K A

    1985-01-01

    Adolescent drug use is placed in an historical and developmental perspective. Existing evidence concerning causes and consequences of adolescent drug use is inconclusive. In the absence of conclusive empirical evidence and cogent theories, we present a prima facie case against early adolescent drug use by defending six propositions which posit specific cognitive, conative, and affective negative consequences including impairment of attention and memory; developmental lag imposing categorical limitations on the level of maximum functioning available to the user in cognitive, moral and psychosocial domains; amotivational syndrome; consolidation of diffuse or negative identity; and social alienation and estrangement. We call for a program of research which could provide credible evidence to support or rebut these propositions, and thus address the factual claims underlying the sociomoral concerns of social policy planners. PMID:4013874

  19. Open Source Drug Discovery in Practice: A Case Study

    PubMed Central

    Årdal, Christine; Røttingen, John-Arne

    2012-01-01

    Background Open source drug discovery offers potential for developing new and inexpensive drugs to combat diseases that disproportionally affect the poor. The concept borrows two principle aspects from open source computing (i.e., collaboration and open access) and applies them to pharmaceutical innovation. By opening a project to external contributors, its research capacity may increase significantly. To date there are only a handful of open source R&D projects focusing on neglected diseases. We wanted to learn from these first movers, their successes and failures, in order to generate a better understanding of how a much-discussed theoretical concept works in practice and may be implemented. Methodology/Principal Findings A descriptive case study was performed, evaluating two specific R&D projects focused on neglected diseases. CSIR Team India Consortium's Open Source Drug Discovery project (CSIR OSDD) and The Synaptic Leap's Schistosomiasis project (TSLS). Data were gathered from four sources: interviews of participating members (n = 14), a survey of potential members (n = 61), an analysis of the websites and a literature review. Both cases have made significant achievements; however, they have done so in very different ways. CSIR OSDD encourages international collaboration, but its process facilitates contributions from mostly Indian researchers and students. Its processes are formal with each task being reviewed by a mentor (almost always offline) before a result is made public. TSLS, on the other hand, has attracted contributors internationally, albeit significantly fewer than CSIR OSDD. Both have obtained funding used to pay for access to facilities, physical resources and, at times, labor costs. TSLS releases its results into the public domain, whereas CSIR OSDD asserts ownership over its results. Conclusions/Significance Technically TSLS is an open source project, whereas CSIR OSDD is a crowdsourced project. However, both have enabled high quality

  20. Quantitative bioanalysis: an integrated approach for drug discovery and development

    NASA Astrophysics Data System (ADS)

    Ong, Voon S.; Cook, Kevin L.; Kosara, Christine M.; Brubaker, William F.

    2004-11-01

    An integrated approach to quantitative bioanalysis, incorporating turbulent flow chromatography (TFC) with mass spectrometric detection, was developed to support in-house drug discovery and development efforts. Activities such as metabolic stability screening and pharmacokinetic characterization support are carried out on a single unified platform. Two different TFC column-switching configurations, parallel and serial, are presented. The first, a parallel TFC column configuration, is capable of high-throughput analysis but carryover can reach as high as 0.24%. The characteristics of the instrument operating in the parallel configuration are provided for analysis of samples generated during in vitro metabolic stability assessments, a key screen during the lead optimization phase of drug discovery. Operating in this configuration, the system has the capability of performing on-line solid phase extraction and analysis of approximately 400 samples containing phosphate-buffered saline in approximately 14 h. The second, a serial TFC column configuration, was used to perform direct plasma injection analysis. The advantage of the serial configuration is the relatively low carryover (<0.040%) observed due to increased number of valve washes; however these extra washes lead to increased injection cycle times. A method developed using the serial TFC column configuration for the determination of dihydropyridines in plasma samples is given as an example. Analytical performance criteria examined during method development and validation included linearity, accuracy, precision, and recovery. The robustness of the technique was demonstrated by applying the method in the analysis of over 2500 plasma samples generated during preclinical drug development studies. Further, combined analysis of plasma and brain tissue was performed using acetonitrile precipitation as sample pretreatment for both matrices.

  1. Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery

    PubMed Central

    Eishingdrelo, Haifeng; Kongsamut, Sathapana

    2013-01-01

    It has become clear in recent years that multiple signal transduction pathways are employed upon GPCR activation. One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinase (ERK). Both G-protein and β-arrestin mediated signaling pathways can lead to ERK activation. However, depending on activation pathway, the subcellular destination of activated ERK1/2 may be different. G-protein -dependent ERK activation results in the translocation of active ERK to the nucleus, whereas ERK activated via an arrestin-dependent mechanism remains largely in the cytoplasm. The subcellular location of activated ERK1/2 determines the downstream signaling cascade. Many substrates of ERK1/2 are found in the nucleus: nuclear transcription factors that participate in gene transcription, cell proliferation and differentiation. ERK1/2 substrates are also found in cytosol and other cellular organelles: they may play roles in translation, mitosis, apoptosis and cross-talk with other signaling pathways. Therefore, determining specific subcellular locations of activated ERK1/2 mediated by GPCR ligands would be important in correlating signaling pathways with cellular physiological functions. While GPCR-stimulated selective ERK pathway activation has been studied in several receptor systems, exploitation of these different signaling cascades for therapeutics has not yet been seriously pursued. Many old drug candidates were identified from screens based on G-protein signaling assays, and their activity on β-arrestin signaling pathways being mostly unknown, especially regarding their subcellular ERK pathways. With today’s knowledge of complicated GPCR signaling pathways, drug discovery can no longer rely on single-pathway approaches. Since ERK activation is an important signaling pathway and associated with many physiological functions, targeting the ERK pathway, especially specific subcellular activation pathways should provide new avenues for GPCR drug

  2. Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery

    PubMed Central

    Peetla, Chiranjeevi; Stine, Andrew; Labhasetwar, Vinod

    2009-01-01

    The transport of drugs or drug delivery systems across the cell membrane is a complex biological process, often difficult to understand because of its dynamic nature. In this regard, model lipid membranes, which mimic many aspects of cell-membrane lipids, have been very useful in helping investigators to discern the roles of lipids in cellular interactions. One can use drug-lipid interactions to predict pharmacokinetic properties of drugs, such as their transport, biodistribution, accumulation, and hence efficacy. These interactions can also be used to study the mechanisms of transport, based on the structure and hydrophilicity/hydrophobicity of drug molecules. In recent years, model lipid membranes have also been explored to understand their mechanisms of interactions with peptides, polymers, and nanocarriers. These interaction studies can be used to design and develop efficient drug delivery systems. Changes in the lipid composition of cells and tissue in certain disease conditions may alter biophysical interactions, which could be explored to develop target-specific drugs and drug delivery systems. In this review, we discuss different model membranes, drug-lipid interactions and their significance, studies of model membrane interactions with nanocarriers, and how biophysical interaction studies with lipid model membranes could play an important role in drug discovery and drug delivery. PMID:19432455

  3. AutoDrug: fully automated macromolecular crystallography workflows for fragment-based drug discovery

    PubMed Central

    Tsai, Yingssu; McPhillips, Scott E.; González, Ana; McPhillips, Timothy M.; Zinn, Daniel; Cohen, Aina E.; Feese, Michael D.; Bushnell, David; Tiefenbrunn, Theresa; Stout, C. David; Ludaescher, Bertram; Hedman, Britt; Hodgson, Keith O.; Soltis, S. Michael

    2013-01-01

    AutoDrug is software based upon the scientific workflow paradigm that integrates the Stanford Synchrotron Radiation Lightsource macromolecular crystallography beamlines and third-party processing software to automate the crystallo­graphy steps of the fragment-based drug-discovery process. AutoDrug screens a cassette of fragment-soaked crystals, selects crystals for data collection based on screening results and user-specified criteria and determines optimal data-collection strategies. It then collects and processes diffraction data, performs molecular replacement using provided models and detects electron density that is likely to arise from bound fragments. All processes are fully automated, i.e. are performed without user interaction or supervision. Samples can be screened in groups corresponding to particular proteins, crystal forms and/or soaking conditions. A single AutoDrug run is only limited by the capacity of the sample-storage dewar at the beamline: currently 288 samples. AutoDrug was developed in conjunction with RestFlow, a new scientific workflow-automation framework. RestFlow simplifies the design of AutoDrug by managing the flow of data and the organization of results and by orchestrating the execution of computational pipeline steps. It also simplifies the execution and interaction of third-party programs and the beamline-control system. Modeling AutoDrug as a scientific workflow enables multiple variants that meet the requirements of different user groups to be developed and supported. A workflow tailored to mimic the crystallography stages comprising the drug-discovery pipeline of CoCrystal Discovery Inc. has been deployed and successfully demonstrated. This workflow was run once on the same 96 samples that the group had examined manually and the workflow cycled successfully through all of the samples, collected data from the same samples that were selected manually and located the same peaks of unmodeled density in the resulting difference

  4. Microfluidics for Drug Discovery and Development: From Target Selection to Product Lifecycle Management

    PubMed Central

    Kang, Lifeng; Chung, Bong Geun; Langer, Robert; Khademhosseini, Ali

    2009-01-01

    Microfluidic technologies’ ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies, and product management. PMID:18190858

  5. Microfluidics for drug discovery and development: from target selection to product lifecycle management.

    PubMed

    Kang, Lifeng; Chung, Bong Geun; Langer, Robert; Khademhosseini, Ali

    2008-01-01

    Microfluidic technologies' ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies and product management. PMID:18190858

  6. Quantum dots and other nanoparticles: what can they offer to drug discovery?

    PubMed

    Ozkan, Mihrimah

    2004-12-15

    Nanocrystals (quantum dots) and other nanoparticles (gold colloids, magnetic bars, nanobars, dendrimers and nanoshells) have been receiving a lot of attention recently with their unique properties for potential use in drug discovery, bioengineering and therapeutics. In this review, structural, optical and biological assets of nanocrystals are summarized and their applications to drug discovery studies are discussed. Unique properties of these nanoparticles can offer new advancements in drug discovery. PMID:15582795

  7. Early drug discovery and the rise of pharmaceutical chemistry.

    PubMed

    Jones, Alan Wayne

    2011-06-01

    Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history. PMID:21698778

  8. [Use of GWAS for drug discovery and development].

    PubMed

    Liou, Shyh-Yuh

    2014-01-01

    The Human Genome Project was completed in 2003. A catalog of common genetic variants in humans was built at the International HapMap Project. These variants, known as single nucleotide polymorphisms (SNPs), occur in human DNA and distributed among populations in different parts of the world. By using the Linkage Disequilibrium and mapping blocks are able to define quantitative characters of inherited diseases. Currently 50 K-5.0 M microarray are available commercially, which based on the results of following the ENCODE & 1000 genome projects. Therefore the genome wide association study (GWAS) has become a key tool for discovering variants that contribute to human diseases and provide maximum coverage of the genome, in contrast to the traditional approach in which only a few candidates genes was targeted. The available public GWAS databases provided valuable biological insights and new discovery for many common diseases, due to the availability of low cost microarray. The GWAS has the potential to provide a solution for the lack of new drug targets and reducing drug failure due to adverse drug reactions either. These are critical issues for pharmaceutical companies. Here, the Japan PGx Data Science Consortium (JPDSC), which was established on February 20, 2009 by six leading pharmaceutical companies in Japan, was introduced. We believe that the efforts of stakeholders including the regulatory authorities, health providers, and pharmaceutical companies to understand the potential and ethical risk of using genetic information including GWAS will bring benefits to patients in the future. PMID:24694807

  9. Recent advances in combinatorial biosynthesis for drug discovery

    PubMed Central

    Sun, Huihua; Liu, Zihe; Zhao, Huimin; Ang, Ee Lui

    2015-01-01

    Because of extraordinary structural diversity and broad biological activities, natural products have played a significant role in drug discovery. These therapeutically important secondary metabolites are assembled and modified by dedicated biosynthetic pathways in their host living organisms. Traditionally, chemists have attempted to synthesize natural product analogs that are important sources of new drugs. However, the extraordinary structural complexity of natural products sometimes makes it challenging for traditional chemical synthesis, which usually involves multiple steps, harsh conditions, toxic organic solvents, and byproduct wastes. In contrast, combinatorial biosynthesis exploits substrate promiscuity and employs engineered enzymes and pathways to produce novel “unnatural” natural products, substantially expanding the structural diversity of natural products with potential pharmaceutical value. Thus, combinatorial biosynthesis provides an environmentally friendly way to produce natural product analogs. Efficient expression of the combinatorial biosynthetic pathway in genetically tractable heterologous hosts can increase the titer of the compound, eventually resulting in less expensive drugs. In this review, we will discuss three major strategies for combinatorial biosynthesis: 1) precursor-directed biosynthesis; 2) enzyme-level modification, which includes swapping of the entire domains, modules and subunits, site-specific mutagenesis, and directed evolution; 3) pathway-level recombination. Recent examples of combinatorial biosynthesis employing these strategies will also be highlighted in this review. PMID:25709407

  10. Matrix metalloproteinase inhibitor development and the remodeling of drug discovery.

    PubMed

    Peterson, J Thomas

    2004-01-01

    Collagen turnover is a slow process on a biologic timescale with a t$\\\\frac12$ of 20-27 days that is mediated primarily by the matrix metalloproteinases (MMPs). Low collagen metabolism is not due to an intrinsically low Km of MMPs, but rather due to a highly regulated system of activity. Despite the stability of collagen and MMPs, the articles in this special addition illustrate the importance of this enzyme family in the disease process leading to congestive heart failure. Like MMPs, drug development is a tightly regulated process, and the successful turnover of MMP inhibitors into a marketed drug has also been a slow process on a pharmaceutical timescale. Since the discovery of the archetypal MMP (type 1 collagenase) over four decades ago by Gross and Lapierre, most major pharmaceutical companies have had MMP inhibitor programs for a variety of indications. Despite decades of research, tens of thousands of compounds synthesized and screened, and billions of dollars spent in clinical studies-Periostat (doxycycline hyclate, CollaGenex Pharmaceuticals Inc.) is the only collagenase inhibitor to be successfully launched. In addition, Periostat's approval is currently limited to periodontal disease. This article focuses on some of the lessons to be learned from the failure of so many MMP inhibitors across so many indications, and what potential exists for MMP inhibitors as a drug class, especially for heart failure. PMID:14739769

  11. Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery.

    PubMed

    Wager, Travis T; Hou, Xinjun; Verhoest, Patrick R; Villalobos, Anabella

    2016-06-15

    Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development. PMID:26991242

  12. Current approaches in antiviral drug discovery against the Flaviviridae family.

    PubMed

    Baharuddin, Aida; Hassan, Asfarina Amir; Sheng, Gan Chye; Nasir, Shah Bakhtiar; Othman, Shatrah; Yusof, Rohana; Othman, Rozana; Rahman, Noorsaadah Abdul

    2014-01-01

    Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed. PMID:24001228

  13. Miniaturized Cultivation of Microbiota for Antimalarial Drug Discovery.

    PubMed

    Waterman, Carrie; Calcul, Laurent; Beau, Jeremy; Ma, Wai Sheung; Lebar, Matthew D; von Salm, Jacqueline L; Harter, Charles; Mutka, Tina; Morton, Lindsay C; Maignan, Patrick; Barisic, Betty; van Olphen, Alberto; Kyle, Dennis E; Vrijmoed, Lilian; Pang, Ka-Lai; Pearce, Cedric J; Baker, Bill J

    2016-01-01

    The ongoing search for effective antiplasmodial agents remains essential in the fight against malaria worldwide. Emerging parasitic drug resistance places an urgent need to explore chemotherapies with novel structures and mechanisms of action. Natural products have historically provided effective antimalarial drug scaffolds. In an effort to search nature's chemical potential for antiplasmodial agents, unconventionally sourced organisms coupled with innovative cultivation techniques were utilized. Approximately 60,000 niche microbes from various habitats (slow-growing terrestrial fungi, Antarctic microbes, and mangrove endophytes) were cultivated on a small-scale, extracted, and used in high-throughput screening to determine antimalarial activity. About 1% of crude extracts were considered active and 6% partially active (≥ 67% inhibition at 5 and 50 μg/mL, respectively). Active extracts (685) were cultivated on a large-scale, fractionated, and screened for both antimalarial activity and cytotoxicity. High interest fractions (397) with an IC50 < 1.11 μg/mL were identified and subjected to chromatographic separation for compound characterization and dereplication. Identifying active compounds with nanomolar antimalarial activity coupled with a selectivity index tenfold higher was accomplished with two of the 52 compounds isolated. This microscale, high-throughput screening project for antiplasmodial agents is discussed in the context of current natural product drug discovery efforts. PMID:25545963

  14. Proteomics. Making sense of genomic information for drug discovery.

    PubMed

    Whitelegge, J P; le Coutre, J

    2001-01-01

    As an increasing number of available genomes triggers a gold rush in modern biology, the scientific challenge shifts towards understanding the total of the encoded information, most notably the proteins, their structures, functions and interactions. Currently this work is in its early stages but the near future will bring a merger of biology, engineering and informatics with a far broader impact on society than pure genomics has had so far. The challenge of characterizing the structures and functions of all proteins in a given cell demands technological advances beyond the classical methodologies of protein biochemistry. Mass spectrometry techniques for high-throughput protein identification, including peptide mass fingerprinting, sequence tagging and mass spectrometry on full-length proteins are providing the driving force behind proteomics endeavors. New technologies are needed to move high-resolution protein structure determination to an industrial scale. Nonetheless, improvements in techniques for the separation of intrinsic membrane proteins are enabling proteomics efforts towards identifying drug targets within this important class of biomolecules. Beyond the acquisition of data on sequences, structures and interactions, however, the major work in drug discovery remains: the screening of large candidate compound libraries combined with clever medicinal chemistry that guarantees selective action and defined delivery of the drug. PMID:12173311

  15. Existing drugs and their application in drug discovery targeting cancer stem cells.

    PubMed

    Lv, Junfang; Shim, Joong Sup

    2015-09-01

    Despite standard cancer therapies such as chemotherapy and targeted therapy have shown some efficacies, the cancer in many cases eventually relapses and metastasizes upon stopping the treatment. There is a small subpopulation of cancer cells within tumor, with specific characters similar to those found in stem cells. This group of cancer cells is known as tumor-initiating or cancer stem cells (CSCs), which have an ability to self-renew and give rise to cancer cell progeny. CSCs are related with drug resistance, metastasis and relapse of cancer, hence emerging as a crucial drug target for eliminating cancer. Rapid advancement of CSC biology has enabled researchers to isolate and culture CSCs in vitro, making the cells amenable to high-throughput drug screening. Recently, drug repositioning, which utilizes existing drugs to develop potential new indications, has been gaining popularity as an alternative approach for the drug discovery. As existing drugs have favorable bioavailability and safety profiles, drug repositioning is now actively exploited for prompt development of therapeutics for many serious diseases, such as cancer. In this review, we will introduce latest examples of attempted drug repositioning targeting CSCs and discuss potential use of the repositioned drugs for cancer therapy. PMID:26152874

  16. Animal models in the drug discovery pipeline for Alzheimer's disease

    PubMed Central

    Van Dam, Debby; De Deyn, Peter Paul

    2011-01-01

    With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371009

  17. Next Generation Sequencing: Potential and Application in Drug Discovery

    PubMed Central

    Yadav, Navneet Kumar; Shukla, Pooja; Omer, Ankur; Pareek, Shruti; Singh, R. K.

    2014-01-01

    The world has now entered into a new era of genomics because of the continued advancements in the next generation high throughput sequencing technologies, which includes sequencing by synthesis-fluorescent in situ sequencing (FISSEQ), pyrosequencing, sequencing by ligation using polony amplification, supported oligonucleotide detection (SOLiD), sequencing by hybridization along with sequencing by ligation, and nanopore technology. Great impacts of these methods can be seen for solving the genome related problems of plant and animal kingdom that will open the door of a new era of genomics. This may ultimately overcome the Sanger sequencing that ruled for 30 years. NGS is expected to advance and make the drug discovery process more rapid. PMID:24688432

  18. Regenerative Medicine: Transforming the Drug Discovery and Development Paradigm

    PubMed Central

    Karathanasis, Sotirios K.

    2014-01-01

    Despite the explosion of knowledge in basic biological processes controlling tissue regeneration and the growing interest in repairing/replacing diseased tissues and organs through various approaches (e.g., small and large molecule therapeutics, stem cell injection, tissue engineering), the pharmaceutical industry (pharma) has been reluctant to fully adopt these technologies into the traditional drug discovery and research and development (R&D) process. In this article, I discuss knowledge-base gaps and other possible factors that may delay full incorporation of these innovations in pharma R&D. I hope that this discussion will illuminate key issues that currently limit synergistic relationships between pharma and academic institutions and may even stimulate initiation of such collaborative research. PMID:25085955

  19. Utilizing diversity-oriented synthesis in antimicrobial drug discovery.

    PubMed

    Comer, Eamon; Duvall, Jeremy R; duPont Lee, Maurice

    2014-01-01

    The development of resistance to existing antimicrobials has created a threat to human health that is not being addressed through our current drug pipeline. Limitations with the use of commercial vendor libraries and natural products have created a need for new types of small molecules to be screened in antimicrobial assays. Diversity oriented synthesis (DOS) is a strategy for the efficient generation of compound collections with a high degree of structural diversity. Diversity-oriented synthesis molecules occupy the middle ground of both complexity and efficiency of synthesis between natural products and commercial libraries. In this review we focus upon the use of diversity-oriented synthesis compound collections for the discovery of new antimicrobial agents. PMID:25495985

  20. SFC/MS in drug discovery at Pfizer, La Jolla

    NASA Astrophysics Data System (ADS)

    Bolaños, Ben; Greig, Michael; Ventura, Manuel; Farrell, William; Aurigemma, Christine M.; Li, Haitao; Quenzer, Terri L.; Tivel, Kathleen; Bylund, Jessica M. R.; Tran, Phuong; Pham, Catherine; Phillipson, Doug

    2004-11-01

    We report the use of supercritical fluid chromatography/mass spectrometry (SFC/MS) for numerous applications in drug discovery at Pfizer, La Jolla. Namely, SFC/MS has been heavily relied upon for analysis and purification of a diverse set of compounds from the in-house chemical library. Supporting high-speed SFC/MS quality control of the purified compounds is made possible at high flow rate SFC along with time-of-flight mass detection. The flexibility of SFC/MS systems has been extended with the integration of an atmospheric pressure photoionization source (APPI) for use with more non-polar compounds and enhancements in signal to noise. Further SFC/MS applications of note include chiral analysis for purification and assessment of enantiomers and SFC/MS analysis of difficult to separate hydrophobic peptides.

  1. Native Mass Spectrometry in Fragment-Based Drug Discovery.

    PubMed

    Pedro, Liliana; Quinn, Ronald J

    2016-01-01

    The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein-ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established utility for fragment-based drug discovery (FBDD). Native MS has the capability to directly detect weak ligand binding to proteins, to determine stoichiometry, relative or absolute binding affinities and specificities. Native MS can be used to delineate ligand-binding sites, to elucidate mechanisms of cooperativity and to study the thermodynamics of binding. This review highlights key attributes of native MS for FBDD campaigns. PMID:27483215

  2. DenguePredict: An Integrated Drug Repositioning Approach towards Drug Discovery for Dengue

    PubMed Central

    Wang, QuanQiu; Xu, Rong

    2015-01-01

    Dengue is a viral disease of expanding global incidence without cures. Here we present a drug repositioning system (DenguePredict) leveraging upon a unique drug treatment database and vast amounts of disease- and drug-related data. We first constructed a large-scale genetic disease network with enriched dengue genetics data curated from biomedical literature. We applied a network-based ranking algorithm to find dengue-related diseases from the disease network. We then developed a novel algorithm to prioritize FDA-approved drugs from dengue-related diseases to treat dengue. When tested in a de-novo validation setting, DenguePredict found the only two drugs tested in clinical trials for treating dengue and ranked them highly: chloroquine ranked at top 0.96% and ivermectin at top 22.75%. We showed that drugs targeting immune systems and arachidonic acid metabolism-related apoptotic pathways might represent innovative drugs to treat dengue. In summary, DenguePredict, by combining comprehensive disease- and drug-related data and novel algorithms, may greatly facilitate drug discovery for dengue. PMID:26958268

  3. Current approaches for the discovery of drugs that deter substance and drug abuse

    PubMed Central

    Yasgar, Adam; Simeonov, Anton

    2015-01-01

    Introduction Much has been presented and debated on the topic of drug abuse and its multidimensional nature, including the role of society and its customs and laws, economical factors, and the magnitude and nature of the burden. Given the complex nature of the receptors and pathways implicated in regulation of the cognitive and behavioral processes associated with addiction, a large number of molecular targets have been interrogated during recent years to discover starting points for development of small molecule interventions. Areas covered This review describes recent developments in the field of early drug discovery for drug abuse interventions, with a special emphasis on advances published during the 2012-2014 period. Expert Opinion Technologically, the processes/platforms utilized in drug abuse drug discovery are nearly identical to those used in the other disease areas. A key complicating factor in drug abuse research is the enormous biological complexity surrounding the brain processes involved and the associated difficulty in finding “good” targets and achieving exquisite selectivity of treatment agents. While tremendous progress has been made during recent years to use the power of high-throughput technologies to discover proof-of-principle molecules for many new targets, next-generation models will be especially important in this field; examples include seeking advantageous drug-drug combinations, use of automated whole-animal behavioral screening systems, advancing our understanding of the role of epigenetics in drug addiction, and the employment of organoid-level 3D test platforms (also referred to as tissue-chip or organs-on-chip). PMID:25251069

  4. Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

    PubMed Central

    Taylor, Christina M.; Wang, Qi; Rosa, Bruce A.; Huang, Stanley Ching-Cheng; Powell, Kerrie; Schedl, Tim; Pearce, Edward J.; Abubucker, Sahar; Mitreva, Makedonka

    2013-01-01

    Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery

  5. 2013 Philip S. Portoghese Medicinal Chemistry Lectureship: Drug Discovery Targeting Allosteric Sites†

    PubMed Central

    2015-01-01

    The identification of sites on receptors topographically distinct from the orthosteric sites, so-called allosteric sites, has heralded novel approaches and modes of pharmacology for target modulation. Over the past 20 years, our understanding of allosteric modulation has grown significantly, and numerous advantages, as well as caveats (e.g., flat structure–activity relationships, species differences, “molecular switches”), have been identified. For multiple receptors and proteins, numerous examples have been described where unprecedented levels of selectivity are achieved along with improved physiochemical properties. While not a panacea, these novel approaches represent exciting opportunities for tool compound development to probe the pharmacology and therapeutic potential of discrete molecular targets, as well as new medicines. In this Perspective, in commemoration of the 2013 Philip S. Portoghese Medicinal Chemistry Lectureship (LindsleyC. W.Adventures in allosteric drug discovery. Presented at the 246th National Meeting of the American Chemical Society, Indianapolis, IN, September 10, 2013; The 2013 Portoghese Lectureship), several vignettes of drug discovery campaigns targeting novel allosteric mechanisms will be recounted, along with lessons learned and guidelines that have emerged for successful lead optimization. PMID:25180768

  6. Drug-drug Interaction Discovery Using Abstraction Networks for “National Drug File – Reference Terminology” Chemical Ingredients

    PubMed Central

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File – Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT’s Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.’s DDI knowledgebase. PMID:26958234

  7. Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors.

    PubMed

    Reid, Terry-Elinor; Fortunak, Joseph M; Wutoh, Anthony; Simon Wang, Xiang

    2016-01-01

    Receptor Tyrosine Kinases (RTKs) are essential components for regulating cell-cell signaling and communication events in cell growth, proliferation, differentiation, survival and metabolism. Deregulation of RTKs and their associated signaling pathways can lead to a wide variety of human diseases such as immunodeficiency, diabetes, arterosclerosis, psoriasis and cancer. Thus RTKs have become one of the most important drug targets families in recent decade. Pharmaceutical companies have dedicated their research efforts towards the discovery of small-molecule inhibitors of RTKs, many of which had been approved by the U.S. Food and Drug Administration (US FDA) or are currently in clinical trials. The great successes in the development of small-molecule inhibitors of RTKs are largely attributed to the use of modern cheminformatic approaches to identifying lead scaffolds. Those include the quantitative structure-activity relationship (QSAR) modeling, as well as the structure-, and ligand-based pharmacophore modeling techniques in this case. Herein we inspected the literature thoroughly in an effort to conduct a comparative analysis of major findings regarding the essential structure-activity relationships (SARs)/pharmacophore features of known active RTK inhibitors, most of which were collected from cheminformatic modeling approaches. PMID:26369823

  8. Tuberculosis drug discovery in the post-post-genomic era

    PubMed Central

    Lechartier, Benoit; Rybniker, Jan; Zumla, Alimuddin; Cole, Stewart T

    2014-01-01

    The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post-genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target-based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be ‘promiscuous’ as they were inhibited by a variety of different compounds. In the post-post-genomics era, more advanced technologies have been implemented and these include high-content screening, screening for inhibitors of latency, the use of conditional knock-down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options. PMID:24401837

  9. Applications of Fiberoptics-Based Nanosensors to Drug Discovery

    PubMed Central

    Vo-Dinh, Tuan; Scaffidi, Jonathan; Gregas, Molly; Zhang, Yan; Seewaldt, Victoria

    2013-01-01

    Background Fiber-optic nanosensors are fabricated by heating and pulling optical fibers to yield sub-micron diameter tips, and have been used for in vitro analysis of individual living mammalian cells. Immobilization of bioreceptors (e.g., antibodies, peptides, DNA, etc) selective to target analyte molecules of interest provides molecular specificity. Excitation light can be launched into the fiber, and the resulting evanescent field at the tip of the nanofiber can be used to excite target molecules bound to the bioreceptor molecules. The fluorescence or surface-enhanced Raman scattering produced by the analyte molecules is detected using an ultra-sensitive photodetector. Objective This article provides an overview of the development and application of fiber-optic nanosensors for drug discovery. Conclusions The nanosensors provide minimally invasive tools to probe sub-cellular compartments inside single living cells for health effect studies (e.g., detection of benzopyrene adducts) and medical applications (e.g., monitoring of apoptosis in cells treated with anti-cancer drugs). PMID:23496274

  10. Winning the arms race by improving drug discovery against mutating targets.

    PubMed

    Anderson, Amy C

    2012-02-17

    Enzymes are often excellent drug targets. Yet drug pressure on an enzyme target often fosters the rise of cells with resistance-conferring mutations, some of which may compromise fitness and others that compensate to restore fitness. This review presents, first, a structural analysis of a diverse group of wild-type and mutant enzyme targets and, second, an in-depth analysis of five diverse targets to elucidate a broader perspective of the effects of resistance-conferring mutations on protein or organismal fitness. The structural analysis reveals that resistance-conferring mutations may introduce steric hindrance or eliminate critical interactions, as expected, but that they may also have indirect effects such as altering protein dynamics and enzyme kinetics. The structure-based development of the latest generation of inhibitors targeting HIV reverse transcriptase, P. falciparum and S. aureus dihydrofolate reductase, neuraminidase, and epithelial growth factor receptor (EGFR) tyrosine kinase, is highlighted to emphasize lessons that may be applied to future drug discovery to overcome mutation-induced resistance. Successful next-generation drugs tend to be more flexible and exploit a greater number of interactions mimicking those of the substrate with conserved residues. PMID:22050347

  11. Is there a best strategy for drug discovery?--SMR Meeting. 13 March 2003, London, UK.

    PubMed

    Lunec, Anna

    2003-05-01

    This gathering of members from academia and industry allowed the sharing of ideas and techniques or the acceleration of drug discovery, and it was clear that there is a need for a more streamlined approach to discovery and development. Clearly, new technologies will aid in the discovery process, but the abilities of the human brain to analyze and interpret data should not be overlooked, as many discoveries have been made by chance or as the result of a hunch, and it would be a shame if the advent of artificial intelligence quashed that inquisitive aspect of drug discovery. PMID:12841215

  12. Cloud Infrastructures for In Silico Drug Discovery: Economic and Practical Aspects

    PubMed Central

    Clematis, Andrea; Quarati, Alfonso; Cesini, Daniele; Milanesi, Luciano; Merelli, Ivan

    2013-01-01

    Cloud computing opens new perspectives for small-medium biotechnology laboratories that need to perform bioinformatics analysis in a flexible and effective way. This seems particularly true for hybrid clouds that couple the scalability offered by general-purpose public clouds with the greater control and ad hoc customizations supplied by the private ones. A hybrid cloud broker, acting as an intermediary between users and public providers, can support customers in the selection of the most suitable offers, optionally adding the provisioning of dedicated services with higher levels of quality. This paper analyses some economic and practical aspects of exploiting cloud computing in a real research scenario for the in silico drug discovery in terms of requirements, costs, and computational load based on the number of expected users. In particular, our work is aimed at supporting both the researchers and the cloud broker delivering an IaaS cloud infrastructure for biotechnology laboratories exposing different levels of nonfunctional requirements. PMID:24106693

  13. Cloud infrastructures for in silico drug discovery: economic and practical aspects.

    PubMed

    D'Agostino, Daniele; Clematis, Andrea; Quarati, Alfonso; Cesini, Daniele; Chiappori, Federica; Milanesi, Luciano; Merelli, Ivan

    2013-01-01

    Cloud computing opens new perspectives for small-medium biotechnology laboratories that need to perform bioinformatics analysis in a flexible and effective way. This seems particularly true for hybrid clouds that couple the scalability offered by general-purpose public clouds with the greater control and ad hoc customizations supplied by the private ones. A hybrid cloud broker, acting as an intermediary between users and public providers, can support customers in the selection of the most suitable offers, optionally adding the provisioning of dedicated services with higher levels of quality. This paper analyses some economic and practical aspects of exploiting cloud computing in a real research scenario for the in silico drug discovery in terms of requirements, costs, and computational load based on the number of expected users. In particular, our work is aimed at supporting both the researchers and the cloud broker delivering an IaaS cloud infrastructure for biotechnology laboratories exposing different levels of nonfunctional requirements. PMID:24106693

  14. Scientometrics of drug discovery efforts: pain-related molecular targets

    PubMed Central

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I–III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I–II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009–2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004–2008 period. In addition, publications representing Phase I–III trials of investigational drugs (2009–2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics

  15. Scientometrics of drug discovery efforts: pain-related molecular targets.

    PubMed

    Kissin, Igor

    2015-01-01

    The aim of this study was to make a scientometric assessment of drug discovery efforts centered on pain-related molecular targets. The following scientometric indices were used: the popularity index, representing the share of articles (or patents) on a specific topic among all articles (or patents) on pain over the same 5-year period; the index of change, representing the change in the number of articles (or patents) on a topic from one 5-year period to the next; the index of expectations, representing the ratio of the number of all types of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed over a 5-year period; the total number of articles representing Phase I-III trials of investigational drugs over a 5-year period; and the trial balance index, a ratio of Phase I-II publications to Phase III publications. Articles (PubMed database) and patents (US Patent and Trademark Office database) on 17 topics related to pain mechanisms were assessed during six 5-year periods from 1984 to 2013. During the most recent 5-year period (2009-2013), seven of 17 topics have demonstrated high research activity (purinergic receptors, serotonin, transient receptor potential channels, cytokines, gamma aminobutyric acid, glutamate, and protein kinases). However, even with these seven topics, the index of expectations decreased or did not change compared with the 2004-2008 period. In addition, publications representing Phase I-III trials of investigational drugs (2009-2013) did not indicate great enthusiasm on the part of the pharmaceutical industry regarding drugs specifically designed for treatment of pain. A promising development related to the new tool of molecular targeting, ie, monoclonal antibodies, for pain treatment has not yet resulted in real success. This approach has not yet demonstrated clinical effectiveness (at least with nerve growth factor) much beyond conventional analgesics, when its

  16. Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity

    PubMed Central

    Zingales, Bianca; Miles, Michael A; Moraes, Carolina B; Luquetti, Alejandro; Guhl, Felipe; Schijman, Alejandro G; Ribeiro, Isabela

    2014-01-01

    This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T. cruzi discrete typing units to include in the panel of strains and the number of strains/clones for primary screens and lead compounds. We also consider experimental approaches for in vitro drug assays. The Figure illustrates the current Chagas disease drug-discovery and development landscape. PMID:25317712

  17. Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

    PubMed

    Benson, Neil

    2015-08-01

    Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. PMID:26464089

  18. Flow cytometry systems for drug discovery and development

    NASA Astrophysics Data System (ADS)

    Ransom, John T.; Edwards, Bruce S.; Kuckuck, Frederick W., III; Okun, Alex; Mattox, David K.; Prossnitz, Eric R.; Sklar, Larry A.

    2000-04-01

    HT-PS is a fluidics-based pharmacology platform that uses viable cells and test compounds to rapidly identify active compounds and immediately determine their potency and specificity. Axiom employs this proprietary flow-through fluidics system coupled to a flow cytometer (FCM) as a detection system. Integration of FCM was enabled through a Plug-Flow Coupler (PFC) device that allows mixtures of cells and test compounds to be delivered to the FCM as discrete plugs of samples under positive air pressure. An FCM detector provides the advantages of multi parametric measurements and multiplexed, single cell analyses. Assays that combine two or more compatible, fluorescent bioresponse indicators simultaneously, such as measurements of intracellular pH and Ca2+, are possible. Alternatively, measurements of one or more bioresponses can be performed on several distinct cell populations individually stained with uniquely addressable fluorescent chromophores. These formats enable multiple experiments on a single sample and provide high content information thereby greatly increasing decision-making power regarding the activity, potency and selectivity of a test compound. Development of significant data with several hundred cells enables reduction in all requisite sample volumes. The PFC enables FCM sample analysis rates of at least 10 samples/minute. The data will illustrate HT-PS/PFC/FCM utility in the drug discovery arena.

  19. Animal models of skin disease for drug discovery

    PubMed Central

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa CMA; Huang, Ying-Ying; Yin, Rui; Rakkiyappan, Chandran; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-01-01

    Introduction Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. Areas covered In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Expert opinion Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia. PMID:23293893

  20. Drug Discovery of Antimicrobial Photosensitizers Using Animal Models

    PubMed Central

    Sharma, Sulbha K.; Dai, Tianhong; Kharkwal, Gitika B.; Huang, Ying-Ying; Huang, Liyi; Bil De Arce, Vida J.; Tegos, George P.; Hamblin, Michael R.

    2012-01-01

    , skin abrasions and soft-tissue abscesses. This range of animal models also represents a powerful aid in antimicrobial drug discovery. PMID:21504410

  1. New strategy for drug discovery by large-scale association analysis of molecular networks of different species

    PubMed Central

    Zhang, Bo; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Wu, Ziyin; Zhang, Wenjuan; Yang, Xiaoyan; Gong, Fukai; Li, Yuerong; Chen, Xiaoyu; Gao, Shuo; Chen, Xuetong; Li, Yan; Lu, Aiping; Wang, Yonghua

    2016-01-01

    The development of modern omics technology has not significantly improved the efficiency of drug development. Rather precise and targeted drug discovery remains unsolved. Here a large-scale cross-species molecular network association (CSMNA) approach for targeted drug screening from natural sources is presented. The algorithm integrates molecular network omics data from humans and 267 plants and microbes, establishing the biological relationships between them and extracting evolutionarily convergent chemicals. This technique allows the researcher to assess targeted drugs for specific human diseases based on specific plant or microbe pathways. In a perspective validation, connections between the plant Halliwell-Asada (HA) cycle and the human Nrf2-ARE pathway were verified and the manner by which the HA cycle molecules act on the human Nrf2-ARE pathway as antioxidants was determined. This shows the potential applicability of this approach in drug discovery. The current method integrates disparate evolutionary species into chemico-biologically coherent circuits, suggesting a new cross-species omics analysis strategy for rational drug development. PMID:26912056

  2. Hypermedia and Discovery-Based Learning: A Historical Perspective.

    ERIC Educational Resources Information Center

    Jacobs, Gabriel

    1992-01-01

    Reviews the history of discovery-based learning, including theories of programed learning, the work of B. F. Skinner, and the impact of information technology. Rejection of discovery learning is identified, and the likelihood in the near future of a revolution in education brought about by hypermedia technology is rejected. (47 references) (MES)

  3. Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

    PubMed

    Schadt, S; Simon, S; Kustermann, S; Boess, F; McGinnis, C; Brink, A; Lieven, R; Fowler, S; Youdim, K; Ullah, M; Marschmann, M; Zihlmann, C; Siegrist, Y M; Cascais, A C; Di Lenarda, E; Durr, E; Schaub, N; Ang, X; Starke, V; Singer, T; Alvarez-Sanchez, R; Roth, A B; Schuler, F; Funk, C

    2015-12-25

    Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates. PMID:26407524

  4. Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes.

    PubMed

    Silva, Tiago; Reis, Joana; Teixeira, José; Borges, Fernanda

    2014-05-01

    Alzheimer's disease (AD) is an incapacitating neurodegenerative disease that slowly destroys brain cells. This disease progressively compromises both memory and cognition, culminating in a state of full dependence and dementia. Currently, AD is the main cause of dementia in the elderly and its prevalence in the developed world is increasing rapidly. Classic drugs, such as acetylcholinesterase inhibitors (AChEIs), fail to decline disease progression and display several side effects that reduce patient's adhesion to pharmacotherapy. The past decade has witnessed an increasing focus on the search for novel AChEIs and new putative enzymatic targets for AD, like β- and γ-secretases, sirtuins, caspase proteins and glycogen synthase kinase-3 (GSK-3). In addition, new mechanistic rationales for drug discovery in AD that include autophagy and synaptogenesis have been discovered. Herein, we describe the state-of-the-art of the development of recent enzymatic inhibitors and enhancers with therapeutic potential on the treatment of AD. PMID:24726823

  5. Crystal structures of 11β-hydroxysteroid dehydrogenase type 1 and their use in drug discovery

    PubMed Central

    Thomas, Mark P; Potter, Barry VL

    2014-01-01

    Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11β-hydroxysteroid dehydrogenase type 1 that have been released may aid drug discovery. The crystal structures have been analyzed in terms of the interactions between the protein and the ligands. Despite a variety of structurally different inhibitors the crystal structures of the proteins are quite similar. However, the differences are significant for drug discovery. The crystal structures can be of use in drug discovery, but care needs to be taken when selecting structures for use in virtual screening and ligand docking. PMID:21446847

  6. Nuclear magnetic resonance: a key metabolomics platform in the drug discovery process.

    PubMed

    Leenders, Justine; Frédérich, Michel; de Tullio, Pascal

    2015-06-01

    Metabolomics is an innovative tool that is now emerging in the drug discovery process. Indeed, its ability to follow the dynamic perturbations in the metabolome resulting from pathologies but also from drug treatment and or/toxicity is of value for the development of new therapeutic approaches. Nuclear magnetic resonance (NMR) spectroscopy, which is an important analytical technique for several steps of the lead discovery, validation and optimization processes, has been described, together with mass spectrometry (MS) as one of the major platform that could be used for metabolomics studies. This review highlights why NMR could be considered a key tool for the application of metabolomics in drug discovery. PMID:26190682

  7. Open Drug Discovery Teams: A Chemistry Mobile App for Collaboration

    PubMed Central

    Ekins, Sean; Clark, Alex M; Williams, Antony J

    2012-01-01

    Abstract The Open Drug Discovery Teams (ODDT) project provides a mobile app primarily intended as a research topic aggregator of predominantly open science data collected from various sources on the internet. It exists to facilitate interdisciplinary teamwork and to relieve the user from data overload, delivering access to information that is highly relevant and focused on their topic areas of interest. Research topics include areas of chemistry and adjacent molecule-oriented biomedical sciences, with an emphasis on those which are most amenable to open research at present. These include rare and neglected diseases, and precompetitive and public-good initiatives such as green chemistry. The ODDT project uses a free mobile app as user entry point. The app has a magazine-like interface, and server-side infrastructure for hosting chemistry-related data as well as value added services. The project is open to participation from anyone and provides the ability for users to make annotations and assertions, thereby contributing to the collective value of the data to the engaged community. Much of the content is derived from public sources, but the platform is also amenable to commercial data input. The technology could also be readily used in-house by organizations as a research aggregator that could integrate internal and external science and discussion. The infrastructure for the app is currently based upon the Twitter API as a useful proof of concept for a real time source of publicly generated content. This could be extended further by accessing other APIs providing news and data feeds of relevance to a particular area of interest. As the project evolves, social networking features will be developed for organizing participants into teams, with various forms of communication and content management possible. PMID:23198003

  8. Understanding mechanisms of toxicity: Insights from drug discovery research

    SciTech Connect

    Houck, Keith A. Kavlock, Robert J.

    2008-03-01

    Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters. Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments.

  9. Open Drug Discovery Teams: A Chemistry Mobile App for Collaboration.

    PubMed

    Ekins, Sean; Clark, Alex M; Williams, Antony J

    2012-08-01

    The Open Drug Discovery Teams (ODDT) project provides a mobile app primarily intended as a research topic aggregator of predominantly open science data collected from various sources on the internet. It exists to facilitate interdisciplinary teamwork and to relieve the user from data overload, delivering access to information that is highly relevant and focused on their topic areas of interest. Research topics include areas of chemistry and adjacent molecule-oriented biomedical sciences, with an emphasis on those which are most amenable to open research at present. These include rare and neglected diseases, and precompetitive and public-good initiatives such as green chemistry. The ODDT project uses a free mobile app as user entry point. The app has a magazine-like interface, and server-side infrastructure for hosting chemistry-related data as well as value added services. The project is open to participation from anyone and provides the ability for users to make annotations and assertions, thereby contributing to the collective value of the data to the engaged community. Much of the content is derived from public sources, but the platform is also amenable to commercial data input. The technology could also be readily used in-house by organizations as a research aggregator that could integrate internal and external science and discussion. The infrastructure for the app is currently based upon the Twitter API as a useful proof of concept for a real time source of publicly generated content. This could be extended further by accessing other APIs providing news and data feeds of relevance to a particular area of interest. As the project evolves, social networking features will be developed for organizing participants into teams, with various forms of communication and content management possible. PMID:23198003

  10. Drug-symptom networking: Linking drug-likeness screening to drug discovery.

    PubMed

    Xu, Xue; Zhang, Chao; Li, PiDong; Zhang, FeiLong; Gao, Kuo; Chen, JianXin; Shang, HongCai

    2016-01-01

    Understanding the relationships between drugs and symptoms has broad medical consequences, yet a comprehensive description of the drug-symptom associations is currently lacking. Here, 1441 FDA-approved drugs were collected, and PCA was used to extract 122 descriptors which explained 91% of the variance. Then, a k-means++ method was employed to partition the drug dataset into 3 clusters, and 3 corresponding SVDD models (drug-likeness screening models) were constructed with an overall accuracy of up to 95.6%. Furthermore, 6878 herbal molecules from the TcmSP™ database were screened by the above 3 SVDD model to obtain 5309 candidate drug molecules with highly accept classification of 77.19%. To assess the accuracy of the SVDD models, 8559 herbal molecule-symptom co-occurrences were mined from Pubmed abstracts, involving 697 herbal molecules and 314 symptoms. Most of the 697 herbal molecules could be found in the accepted SVDD data (5309 molecules), showing the potential of the SVDD for the screening of drug candidates. Moreover, a herbal molecule-herbal molecule network and a herbal molecule-symptom were constructed. Overall, the results provided a new drug-likeness screening approach independent to abnormal training data, and the comprehensive collection of herbal molecule-symptom associations formed a new data resource for systematic characterization of the symptom-oriented medicines. PMID:26615785

  11. Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery.

    PubMed

    Zhou, Kaixin; Pedersen, Helle Krogh; Dawed, Adem Y; Pearson, Ewan R

    2016-06-01

    Genomic studies have greatly advanced our understanding of the multifactorial aetiology of type 2 diabetes mellitus (T2DM) as well as the multiple subtypes of monogenic diabetes mellitus. In this Review, we discuss the existing pharmacogenetic evidence in both monogenic diabetes mellitus and T2DM. We highlight mechanistic insights from the study of adverse effects and the efficacy of antidiabetic drugs. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A represents a clear example of how pharmacogenetics can direct patient care. However, pharmacogenomic studies of response to antidiabetic drugs in T2DM has yet to be translated into clinical practice, although some moderate genetic effects have now been described that merit follow-up in trials in which patients are selected according to genotype. We also discuss how future pharmacogenomic findings could provide insights into treatment response in diabetes mellitus that, in addition to other areas of human genetics, facilitates drug discovery and drug development for T2DM. PMID:27062931

  12. Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery.

    PubMed

    Lounnas, Valère; Ritschel, Tina; Kelder, Jan; McGuire, Ross; Bywater, Robert P; Foloppe, Nicolas

    2013-01-01

    The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented. PMID:24688704

  13. Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery

    PubMed Central

    Lounnas, Valère; Ritschel, Tina; Kelder, Jan; McGuire, Ross; Bywater, Robert P.; Foloppe, Nicolas

    2013-01-01

    The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented. PMID:24688704

  14. PET and SPECT imaging of the opioid system: receptors, radioligands and avenues for drug discovery and development.

    PubMed

    Lever, John R

    2007-01-01

    As we celebrate the bicentennial of the isolation of morphine by Sertürner, opioids continue to dominate major sectors of the analgesic market worldwide. The pharmaceutical industry stands to benefit greatly from molecular imaging in preclinical and early clinical trials of new or improved opioid drugs. At this juncture, it seems fitting to summarize the past twenty or so years of research on molecular imaging of the opioid system from the viewpoint of drug discovery and development. Opioid receptors were first imaged in human volunteers by positron emission tomography (PET) in 1984. Now, quantitative PET imaging of the major opioid receptor types (micro, delta , kappa) is possible in the brain and peripheral organs of healthy persons and patient populations. Radioligands are under development for single photon emission computed tomography (SPECT) of opioid receptors as well. These functional, nuclear imaging techniques can trace the fate of radiolabeled molecules directly, but non-invasively, and allow precise pharmacokinetic and pharmacodynamic measurements. Molecular imaging provides unique data that can aid in selecting the best drug candidates, determining optimal dosing regimens, clearing regulatory hurdles and lowering risks of failure. Using a historical perspective, this review touches on opioid receptors as drug targets, and focuses on the status and use of radiotracers for opioid receptor PET and SPECT. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development. PMID:17266587

  15. Yeast: a microbe with macro-implications to antimicrobial drug discovery.

    PubMed

    Balibar, Carl J; Roemer, Terry

    2016-03-01

    Paramount to any rational discovery of new antibiotics displaying novel mechanisms of action is a deep knowledge of the genetic basis of microbial growth, division and virulence. The bakers' yeast,Saccharomyces cerevisiae, illustrates the highest understanding of the genetic underpinnings of microbial life, and from this framework, a systems biology paradigm has evolved, begging to be emulated in antibacterial discovery. Here, we review landmark events in the history of yeast genomics that provide this new foundation for antibacterial drug discovery. PMID:26443612

  16. Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery

    PubMed Central

    Zhu, Feng; Shi, Zhe; Qin, Chu; Tao, Lin; Liu, Xin; Xu, Feng; Zhang, Li; Song, Yang; Liu, Xianghui; Zhang, Jingxian; Han, Bucong; Zhang, Peng; Chen, Yuzong

    2012-01-01

    Knowledge and investigation of therapeutic targets (responsible for drug efficacy) and the targeted drugs facilitate target and drug discovery and validation. Therapeutic Target Database (TTD, http://bidd.nus.edu.sg/group/ttd/ttd.asp) has been developed to provide comprehensive information about efficacy targets and the corresponding approved, clinical trial and investigative drugs. Since its last update, major improvements and updates have been made to TTD. In addition to the significant increase of data content (from 1894 targets and 5028 drugs to 2025 targets and 17 816 drugs), we added target validation information (drug potency against target, effect against disease models and effect of target knockout, knockdown or genetic variations) for 932 targets, and 841 quantitative structure activity relationship models for active compounds of 228 chemical types against 121 targets. Moreover, we added the data from our previous drug studies including 3681 multi-target agents against 108 target pairs, 116 drug combinations with their synergistic, additive, antagonistic, potentiative or reductive mechanisms, 1427 natural product-derived approved, clinical trial and pre-clinical drugs and cross-links to the clinical trial information page in the ClinicalTrials.gov database for 770 clinical trial drugs. These updates are useful for facilitating target discovery and validation, drug lead discovery and optimization, and the development of multi-target drugs and drug combinations. PMID:21948793

  17. Open Access High Throughput Drug Discovery in the Public Domain: A Mount Everest in the Making

    PubMed Central

    Roy, Anuradha; McDonald, Peter R.; Sittampalam, Sitta; Chaguturu, Rathnam

    2013-01-01

    High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry’s best practices for a successful outcome. PMID:20809896

  18. Open access high throughput drug discovery in the public domain: a Mount Everest in the making.

    PubMed

    Roy, Anuradha; McDonald, Peter R; Sittampalam, Sitta; Chaguturu, Rathnam

    2010-11-01

    High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry's best practices for a successful outcome. PMID:20809896

  19. Nexus Between Protein–Ligand Affinity Rank-Ordering, Biophysical Approaches, and Drug Discovery

    PubMed Central

    2013-01-01

    The confluence of computational and biophysical methods to accurately rank-order the binding affinities of small molecules and determine structures of macromolecular complexes is a potentially transformative advance in the work flow of drug discovery. This viewpoint explores the impact that advanced computational methods may have on the efficacy of small molecule drug discovery and optimization, particularly with respect to emerging fragment-based methods. PMID:24900579

  20. Whole organism based techniques and approaches in early stage oncology drug discovery-patents and trends.

    PubMed

    Hampson, Richard J; Wyatt, Michael D

    2011-09-01

    Discovery of new cancer drugs is important for the improvement of disease treatment and management. In addition to the clear medical needs there are also economic considerations: Much drug discovery is performed in the private sector. The high cost of some drug treatments, which can run to tens of thousands of US$ per patient for single courses of therapy has led to the perception of high profitability in the industry. But drug discovery and development is a very expensive and lengthy process, with an ongoing trend of fewer drugs brought to market per dollar invested in R&D Biochemical-based in vitro screens for hosts of targets have produced early stage drug candidates and led to drugs reaching the market, but there remains a great need to evaluate in vivo efficacy, toxicity and potential off-target effects as early as possible in the discovery process. Using whole organisms much earlier in cancer (and other) drug discovery is a potential approach to improve R&D productivity. Here, we provide an overview of recent patenting activity and take a brief look at possible new developments in the field. PMID:21913888

  1. Recent discoveries of influenza A drug target sites to combat virus replication.

    PubMed

    Patel, Hershna; Kukol, Andreas

    2016-06-15

    Sequence variations in the binding sites of influenza A proteins are known to limit the effectiveness of current antiviral drugs. Clinically, this leads to increased rates of virus transmission and pathogenicity. Potential influenza A inhibitors are continually being discovered as a result of high-throughput cell based screening studies, whereas the application of computational tools to aid drug discovery has further increased the number of predicted inhibitors reported. This review brings together the aspects that relate to the identification of influenza A drug target sites and the findings from recent antiviral drug discovery strategies. PMID:27284062

  2. Common characteristics of open source software development and applicability for drug discovery: a systematic review

    PubMed Central

    2011-01-01

    Background Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. Methods A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Results Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. Conclusions We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents. PMID:21955914

  3. Perspectives on Preventing Student Drug Abuse.

    ERIC Educational Resources Information Center

    Pedone, Ronald, Ed.; Gwaltney, Margaret K., Ed.

    This set of papers is one part of the United States Department of Education's effort to establish a research agenda for drug use. It consists of a foreword and 10 papers that examine issues of drug abuse, students, and schools. It presents different views on the drug abuse problem in order to affect research on schools, drugs, and drug education.…

  4. Perspectives on the Community College: A Journey of Discovery.

    ERIC Educational Resources Information Center

    Thomas, Noreen, Ed.

    This monograph was designed to provide a comprehensive and enlightened view of the community college as it faces complicated new demands. It offers articles written by community college professionals, including the following: (1) "A Journey of Discovery" by Albert L. Lorenzo; (2) "Organizational Readiness: Middle Age and the Middle Way" by Cindy…

  5. Discovery and Delivery of Synergistic Chemotherapy Drug Combinations to Tumors

    NASA Astrophysics Data System (ADS)

    Camacho, Kathryn Militar

    Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped. Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects. Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts. The advantages of multi-drug incorporation in nano-vehicles are many: improved accumulation in tumor tissue via the enhanced permeation and retention effect, limited uptake in healthy tissue, and controlled exposure of tumor tissue to optimal synergistic drug ratios. To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: liposomes and polymer-drug conjugates. Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios. Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model. Furthermore, versatile drug incorporation methods investigated here can be broadly

  6. Proteomic Approaches in Biomarker Discovery: New Perspectives in Cancer Diagnostics

    PubMed Central

    Kocevar, Nina; Komel, Radovan

    2014-01-01

    Despite remarkable progress in proteomic methods, including improved detection limits and sensitivity, these methods have not yet been established in routine clinical practice. The main limitations, which prevent their integration into clinics, are high cost of equipment, the need for highly trained personnel, and last, but not least, the establishment of reliable and accurate protein biomarkers or panels of protein biomarkers for detection of neoplasms. Furthermore, the complexity and heterogeneity of most solid tumours present obstacles in the discovery of specific protein signatures, which could be used for early detection of cancers, for prediction of disease outcome, and for determining the response to specific therapies. However, cancer proteome, as the end-point of pathological processes that underlie cancer development and progression, could represent an important source for the discovery of new biomarkers and molecular targets for tailored therapies. PMID:24550697

  7. Beyond "Discovery": Lewis & Clark from an Indigenous Perspective.

    ERIC Educational Resources Information Center

    Littlebear, Richard

    2003-01-01

    Recontextualizes the history of the Lewis and Clark expedition from a Native American perspective. Argues that the success of the expedition hastened killing of American Indians and more firmly entrenched U.S. government policies toward indigenous peoples. Stresses that education, particularly at tribal colleges, is the key to success for…

  8. Biodiversity conservation and drug discovery: Can they be combined? The Suriname and Madagascar experiences.

    PubMed

    Cao, Shugeng; Kingston, David G I

    2009-08-01

    The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others.Drug discovery from natural sources requires continued access to plant, marine, and microbial biomass, and so the preservation of tropical rainforests is an important part of our drug discovery program. Sadly, many of the tropical forests of the world are under severe environmental pressure, and deforestation is a serious problem in most tropical countries. One way to combat this loss is to demonstrate their value as potential sources of new pharmaceutical or agrochemical products.As part of an effort to integrate biodiversity conservation and drug discovery with economic development, we initiated an International Cooperative biodiversity Group (ICBG) to discover potential pharmaceuticals from the plant biodiversity of Suriname and Madagascar. The Group, established with funding from agencies of the United States government, involved participants from the USA, Suriname, and Madagascar. The basic approach was to search for bioactive plants in the Suriname and Malagasy flora, and to isolate their bioactive constituents by the best available methods, but the work included capacity building as well as research. Progress on this project will be reported, drawing on results obtained from the isolation of bioactive natural products from Suriname and Madagascar. The benefits of this general approach to biodiversity and drug discovery will also be discussed. PMID:20161050

  9. Biodiversity conservation and drug discovery: Can they be combined? The Suriname and Madagascar experiences

    PubMed Central

    Cao, Shugeng; Kingston, David G. I.

    2009-01-01

    The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others. Drug discovery from natural sources requires continued access to plant, marine, and microbial biomass, and so the preservation of tropical rainforests is an important part of our drug discovery program. Sadly, many of the tropical forests of the world are under severe environmental pressure, and deforestation is a serious problem in most tropical countries. One way to combat this loss is to demonstrate their value as potential sources of new pharmaceutical or agrochemical products. As part of an effort to integrate biodiversity conservation and drug discovery with economic development, we initiated an International Cooperative biodiversity Group (ICBG) to discover potential pharmaceuticals from the plant biodiversity of Suriname and Madagascar. The Group, established with funding from agencies of the United States government, involved participants from the USA, Suriname, and Madagascar. The basic approach was to search for bioactive plants in the Suriname and Malagasy flora, and to isolate their bioactive constituents by the best available methods, but the work included capacity building as well as research. Progress on this project will be reported, drawing on results obtained from the isolation of bioactive natural products from Suriname and Madagascar. The benefits of this general approach to biodiversity and drug discovery will also be discussed. PMID:20161050

  10. Perspectives on the Interface of Drug Delivery and Tissue Engineering

    PubMed Central

    Ekenseair, Adam K.; Kasper, F. Kurtis; Mikos, Antonios G.

    2012-01-01

    Controlled drug delivery of bioactive molecules continues to be an essential component of engineering strategies for tissue defect repair. This article surveys the current challenges associated with trying to regenerate complex tissues utilizing drug delivery and gives perspectives on the development of translational tissue engineering therapies which promote spatiotemporal cell-signaling cascades to maximize the rate and quality of repair. PMID:23000743

  11. Drug discovery research in India: current state and future prospects.

    PubMed

    Balganesh, Tanjore; Kundu, Tapas K; Chakraborty, Tushar Kanti; Roy, Siddhartha

    2014-07-10

    Indian civilization developed a strong system of traditional medicine and was one of the first nations to develop a synthetic drug. In the postindependence era, Indian pharmaceutical industry developed a strong base for production of generic drugs. Challenges for the future are to give its traditional medicine a strong scientific base and develop research and clinical capability to consistently produce new drugs based on advances in modern biological sciences. PMID:25050153

  12. The Life Course Perspective on Drug Use: A Conceptual Framework for Understanding Drug Use Trajectories

    ERIC Educational Resources Information Center

    Hser, Yih-Ing; Longshore, Douglas; Anglin, M. Douglas

    2007-01-01

    This article discusses the life course perspective on drug use, including conceptual and analytic issues involved in developing the life course framework to explain how drug use trajectories develop during an individual's lifetime and how this knowledge can guide new research and approaches to management of drug dependence. Central concepts…

  13. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery.

    PubMed

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  14. canSAR: an updated cancer research and drug discovery knowledgebase

    PubMed Central

    Tym, Joseph E.; Mitsopoulos, Costas; Coker, Elizabeth A.; Razaz, Parisa; Schierz, Amanda C.; Antolin, Albert A.; Al-Lazikani, Bissan

    2016-01-01

    canSAR (http://cansar.icr.ac.uk) is a publicly available, multidisciplinary, cancer-focused knowledgebase developed to support cancer translational research and drug discovery. canSAR integrates genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and druggability data. canSAR is widely used to rapidly access information and help interpret experimental data in a translational and drug discovery context. Here we describe major enhancements to canSAR including new data, improved search and browsing capabilities, new disease and cancer cell line summaries and new and enhanced batch analysis tools. PMID:26673713

  15. Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery

    PubMed Central

    Stewart, Adam Michael; Gerlai, Robert; Kalueff, Allan V.

    2015-01-01

    The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID:25729356

  16. The 2012 Garrod lecture: discovery of antibacterial drugs in the 21st century.

    PubMed

    Chopra, Ian

    2013-03-01

    The discovery and development of antibacterial drugs in the twentieth century were major scientific and medical achievements that have had profound benefits for human society. However, in the twenty-first century the widespread global occurrence of bacteria resistant to the antibiotics and synthetic drugs discovered in the previous century threatens to reverse our ability to treat infectious diseases. Although some new drugs are in development they do not adequately cover growing medical needs. Furthermore, these drugs are mostly derivatives of older classes already in use and therefore prone to existing bacterial resistance mechanisms. Thus, new drug classes are urgently needed. Despite investment in antibacterial drug discovery, no new drug class has been discovered in the past 20 years. In this review, based upon my career as a research scientist in the field of antibacterial drug discovery, I consider some of the technical reasons for the recent failure and look to the future developments that may help to reverse the poor current success rate. Diversification of screening libraries to include new natural products will be important as well as ensuring that the promising drug hits arising from structure-based drug design can achieve effective concentrations at their target sites within the bacterial cell. PMID:23134656

  17. Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

    PubMed Central

    Tzvetkov, Mladen V.

    2008-01-01

    Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance. PMID:18224312

  18. The major impacts of James Black's drug discoveries on medicine and pharmacology.

    PubMed

    Walker, Michael J A

    2011-04-01

    James Black has many claims to pharmacological fame as the creator of two new classes of drugs (beta-blockers and H2 antihistamines) and as a tireless innovator in drug discovery strategies and analytical procedures. The latter attributes in particular assisted Black in the invention of the prototypes for the two major classes of drugs for which he is best known, propranolol and cimetidine. The clinical impact of these drugs on both morbidity and mortality has been profound. In addition, the application of his analytical approach to drug discovery and pharmacology led others in the field to create many other new classes of drugs. Shortly before he died in 2010, Black wrote a retrospective review of his research career that provides insight into his innovative thinking and career success. This overview affords readers a very personal picture of the man, his ideas and his contributions. PMID:21414672

  19. Discovery of drugs that possess activity against feline leukemia virus

    PubMed Central

    Greggs, Willie M.; Clouser, Christine L.; Patterson, Steven E.

    2012-01-01

    Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use. PMID:22258856

  20. Reprint of: Highthroughtput analysis of behavior for drug discovery.

    PubMed

    Alexandrov, Vadim; Brunner, Dani; Hanania, Taleen; Leahy, Emer

    2015-04-15

    Drug testing with traditional behavioral assays constitutes a major bottleneck in the development of novel therapies. PsychoGenics developed three comprehensive highthroughtput systems, SmartCube(®), NeuroCube(®) and PhenoCube(®) systems, to increase the efficiency of the drug screening and phenotyping in rodents. These three systems capture different domains of behavior, namely, cognitive, motor, circadian, social, anxiety-like, gait and others, using custom-built computer vision software and machine learning algorithms for analysis. This review exemplifies the use of the three systems and explains how they can advance drug screening with their applications to phenotyping of disease models, drug screening, selection of lead candidates, behavior-driven lead optimization, and drug repurposing. PMID:25744878

  1. High-throughput analysis of behavior for drug discovery.

    PubMed

    Alexandrov, Vadim; Brunner, Dani; Hanania, Taleen; Leahy, Emer

    2015-03-01

    Drug testing with traditional behavioral assays constitutes a major bottleneck in the development of novel therapies. PsychoGenics developed three comprehensive high-throughput systems, SmartCube(®), NeuroCube(®) and PhenoCube(®) systems, to increase the efficiency of the drug screening and phenotyping in rodents. These three systems capture different domains of behavior, namely, cognitive, motor, circadian, social, anxiety-like, gait and others, using custom-built computer vision software and machine learning algorithms for analysis. This review exemplifies the use of the three systems and explains how they can advance drug screening with their applications to phenotyping of disease models, drug screening, selection of lead candidates, behavior-driven lead optimization, and drug repurposing. PMID:25592319

  2. Drug discovery through stem cell-based organoid models.

    PubMed

    Ranga, Adrian; Gjorevski, Nikolche; Lutolf, Matthias P

    2014-04-01

    The development of new drugs is currently a long and costly process in large part due to the failure of promising drug candidates identified in initial in vitro screens to perform as intended in vivo. New approaches to drug screening are being developed which focus on providing more biomimetic platforms. This review surveys this new generation of drug screening technologies, and provides an overview of recent developments in organoid culture systems which could afford previously unmatched fidelity for testing bioactivity and toxicity. The challenges inherent in such approaches will also be discussed, with a view towards bridging the gap between proof-of-concept studies and a wider implementation within the drug development community. PMID:24582599

  3. Discoveries in oxygenic photosynthesis (1727-2003): a perspective.

    PubMed

    Govindjee; Krogmann, David

    2004-01-01

    We present historic discoveries and important observations, related to oxygenic photosynthesis, from 1727 to 2003. The decision to include certain discoveries while omitting others has been difficult. We are aware that ours is an incomplete timeline. In part, this is because the function of this list is to complement, not duplicate, the listing of discoveries in the other papers in these history issues of Photosynthesis Research. In addition, no one can know everything that is in the extensive literature in the field. Furthermore, any judgement about significance presupposes a point of view. This history begins with the observation of the English clergyman Stephen Hales (1677-1761) that plants derive nourishment from the air; it includes the definitive experiments in the 1960-1965 period establishing the two-photosystem and two-light reaction scheme of oxygenic photosynthesis; and includes the near-atomic resolution of the structures of the reaction centers of these two Photosystems, I and II, obtained in 2001-2002 by a team in Berlin, Germany, coordinated by Horst Witt and Wolfgang Saenger. Readers are directed to historical papers in Govindjee and Gest [(2002a) Photosynth Res 73: 1-308], in Govindjee, J. Thomas Beatty and Howard Gest [(2003a) Photosynth Res 76: 1-462], and to other papers in this issue for a more complete picture. Several photographs are provided here. Their selection is based partly on their availability to the authors (see Figures 1-15). Readers may view other photographs in Part 1 (Volume 73, Photosynth Res, 2002), Part 2 (Volume 76, Photosynth Res, 2003) and Part 3 (Volume 80 Photosynth Res, 2004) of the history issues of Photosynthesis Research. Photographs of most of the Nobel-laureates are included in Govindjee, Thomas Beatty and John Allen, this issue. For a complementary time line of anoxygenic photosynthesis, see H. Gest and R. Blankenship (this issue). PMID:16328809

  4. Exploring the Role of Receptor Flexibility in Structure-Based Drug Discovery

    PubMed Central

    Feixas, Ferran; Lindert, Steffen; Sinko, William; McCammon, J. Andrew

    2015-01-01

    The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads. PMID:24332165

  5. Perspective: Data infrastructure for high throughput materials discovery

    NASA Astrophysics Data System (ADS)

    Pfeif, E. A.; Kroenlein, K.

    2016-05-01

    Computational capability has enabled materials design to evolve from trial-and-error towards more informed methodologies that require large amounts of data. Expert-designed tools and their underlying databases facilitate modern-day high throughput computational methods. Standard data formats and communication standards increase the impact of traditional data, and applying these technologies to a high throughput experimental design provides dense, targeted materials data that are valuable for material discovery. Integrated computational materials engineering requires both experimentally and computationally derived data. Harvesting these comprehensively requires different methods of varying degrees of automation to accommodate variety and volume. Issues of data quality persist independent of type.

  6. Structure-Based Strategies for Drug Design and Discovery

    NASA Astrophysics Data System (ADS)

    Kuntz, Irwin D.

    1992-08-01

    Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors. One source of this information is in the structures of critical proteins and nucleic acids. The structure-based approach to design couples this information with specialized computer programs to propose novel enzyme inhibitors and other therapeutic agents. Iterated design cycles have produced compounds now in clinical trials. The combination of molecular structure determination and computation is emerging as an important tool for drug development. These ideas will be applied to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance.

  7. The clinical pharmacologist in drug regulation: the US perspective.

    PubMed

    Temple, R J

    1996-07-01

    1. Drug development has moved into a new era--a time of particular interest in individualization of treatment and dose-response--that is of particular interest to clinical pharmacologists. 2. Clinical pharmacologists' skills are especially applicable to identifying subgroup differences in pharmacokinetics and the consequences of those differences through such techniques as the pharmacokinetic screen and evaluation of metabolic differences and drug-drug interactions. Clinical pharmacologists also can contribute to the discovery of true differences in pharmacodynamic response. 3. Clinical pharmacologists are trained to take a broad view of drugs, recognizing that they not only have the pharmacologic property of primary interest but often other properties as well, that a 'drug' is really many drugs (isomers, active metabolites) with different properties, and that the properties of drugs should affect how they are dosed and used. PMID:8807147

  8. New directions for protease inhibitors directed drug discovery.

    PubMed

    Hamada, Yoshio; Kiso, Yoshiaki

    2016-11-01

    Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, β-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T-lymphotropic virus type I protease, plasmepsins, and β-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016. PMID:26584340

  9. Can formulation and drug delivery reduce attrition during drug discovery and development—review of feasibility, benefits and challenges

    PubMed Central

    Basavaraj, S; Betageri, Guru V.

    2014-01-01

    Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards “me too” drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years. The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties, lack of efficacy and safety reasons. Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability. The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail. PMID:26579359

  10. Novel Data Mining Methodologies for Adverse Drug Event Discovery and Analysis

    PubMed Central

    Harpaz, Rave; DuMouchel, William; Shah, Nigam H.; Madigan, David; Ryan, Patrick; Friedman, Carol

    2013-01-01

    Introduction Discovery of new adverse drug events (ADEs) in the post-approval period is an important goal of the health system. Data mining methods that can transform data into meaningful knowledge to inform patient safety have proven to be essential. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used in support of ADE discovery and analysis. PMID:22549283

  11. Perspective: Role of structure prediction in materials discovery and design

    NASA Astrophysics Data System (ADS)

    Needs, Richard J.; Pickard, Chris J.

    2016-05-01

    Materials informatics owes much to bioinformatics and the Materials Genome Initiative has been inspired by the Human Genome Project. But there is more to bioinformatics than genomes, and the same is true for materials informatics. Here we describe the rapidly expanding role of searching for structures of materials using first-principles electronic-structure methods. Structure searching has played an important part in unraveling structures of dense hydrogen and in identifying the record-high-temperature superconducting component in hydrogen sulfide at high pressures. We suggest that first-principles structure searching has already demonstrated its ability to determine structures of a wide range of materials and that it will play a central and increasing part in materials discovery and design.

  12. Announcing the discovery of Middle Earth: A dating perspective

    NASA Astrophysics Data System (ADS)

    Turney, C.

    2006-12-01

    In 2003, an Australian and Indonesian research team was excavating in a limestone cave called Liang Bua on the island of Flores when they made a startling discovery: a near complete human skeleton was found at a depth of 5.9 m. The worn teeth indicated that the remains were those of an adult but it was only 1 m tall. When it was dug out of the ground, it was clear the individual wasn't anything like a modern human or any of the other human species that survived until recently. Many features in the skeleton were unusual. Not only was the individual short in stature, but the brain was tiny; the cavity where it once was measured a mere 380 cm3 similar in size to a chimpanzee. Previously, the smallest Homo brain was thought to be around 500 cm3, and this was for the first known species of our genus, Homo habilis, some 2.3 million years ago. The skeleton had many other unusual and ancient features, including a sloping forehead, wide pelvis, arms that reached down to its knees, and multiple-rooted teeth. Although the features were ancient, the age for the find was not. The main skeleton was 18,000 years old. Other remains dated to only 13,000 years ago; geologically speaking this was yesterday. The stone tools found with the remains suggested these little creatures were not stupid; they could think for themselves. When we reported the discovery in October 2004, the scientific name we settled on was Homo floresiensis but the main find became better known as `the Hobbit'. This presentation will describe the immediate maelstrom of public interest and some of the controversy that has ensued.

  13. Discovery and occurrence of the fumonisins: a historical perspective.

    PubMed Central

    Marasas, W F

    2001-01-01

    This article describes the events leading to the discovery of the fumonisins in South Africa in 1988 and highlights the first 10 years (1988-1998) of fumonisin research. The predominant fungus isolated from moldy corn implicated in a field outbreak of equine leukoencephalomalacia (ELEM) in South Africa in 1970 was Fusarium verticillioides (F. moniliforme). This fungus was also prevalent in moldy home-grown corn consumed by people in high-incidence areas of esophageal cancer (EC) in the Transkei region of South Africa. Culture material on corn of F. verticillioides strain MRC 826, which was isolated from moldy corn in Transkei, was shown to cause ELEM in horses, porcine pulmonary edema (PPE) syndrome in pigs, and liver cancer in rats. A short-term cancer initiation/promotion assay in rat liver was used to purify the carcinogen(s) in the culture material. These efforts finally met with success when fumonisins B1 and B2 novel mycotoxins with cancer-promoting activity in rat liver, were isolated from culture material of F. verticillioides MRC 826 at the Programme on Mycotoxins and Experimental Carcinogenesis of the Medical Research Council in Tygerberg, South Africa. Following the elucidation of the chemical structure of the fumonisins, these carcinogenic mycotoxins were shown to occur naturally in moldy corn in Transkei. Shortly thereafter, high levels of fumonisins in the 1989 U.S. corn crop resulted in large-scale field outbreaks of ELEM and PPE in horses and pigs, respectively, in the United States. Subsequently the fumonisins were found to occur naturally in corn worldwide, including corn consumed as the staple diet by people at high risk for EC in Transkei and China. These findings, together with the fact that the fumonisins cause field outbreaks of mycotoxicoses in animals, are carcinogenic in rats, and disrupt sphingolipid metabolism, have resulted in much worldwide interest in these compounds during the first 10 years after the discovery of the fumonisins in

  14. Strategies to support drug discovery through integration of systems and data.

    PubMed

    Waller, Chris L; Shah, Ajay; Nolte, Matthias

    2007-08-01

    Much progress has been made over the past several years to provide technologies for the integration of drug discovery software applications and the underlying data bits. Integration at the application layer has focused primarily on developing and delivering applications that support specific workflows within the drug discovery arena. A fine balance between creating behemoth applications and providing business value must be maintained. Heterogeneous data sources have typically been integrated at the data level in an effort to provide a more holistic view of the data packages supporting key decision points. This review will highlight past attempts, current status, and potential future directions for systems and data integration strategies in support of drug discovery efforts. PMID:17706544

  15. Outsourcing drug discovery to India and China: from surviving to thriving.

    PubMed

    Subramaniam, Swaminathan; Dugar, Sundeep

    2012-10-01

    Global pharmaceutical companies face an increasingly harsh environment for their primary business of selling medicines. They have to contend with a spiraling decline in the productivity of their R&D programs that is guaranteed to severely diminish their growth prospects. Outsourcing of drug discovery activities to low-cost locations is a growing response to this crisis. However, the upsides to outsourcing are capped by the failure of global pharmaceutical companies to take advantage of the full range of possibilities that this model provides. Companies that radically rethink and transform the way they conduct R&D, such as seeking the benefits of low-cost locations in India and China will be the ones that thrive in this environment. In this article we present our views on how the outsourcing model in drug discovery should go beyond increasing the efficiency of existing drug discovery processes to a fundamental rethink and re-engineering of these processes. PMID:22542471

  16. High-throughput imaging: Focusing in on drug discovery in 3D.

    PubMed

    Li, Linfeng; Zhou, Qiong; Voss, Ty C; Quick, Kevin L; LaBarbera, Daniel V

    2016-03-01

    3D organotypic culture models such as organoids and multicellular tumor spheroids (MCTS) are becoming more widely used for drug discovery and toxicology screening. As a result, 3D culture technologies adapted for high-throughput screening formats are prevalent. While a multitude of assays have been reported and validated for high-throughput imaging (HTI) and high-content screening (HCS) for novel drug discovery and toxicology, limited HTI/HCS with large compound libraries have been reported. Nonetheless, 3D HTI instrumentation technology is advancing and this technology is now on the verge of allowing for 3D HCS of thousands of samples. This review focuses on the state-of-the-art high-throughput imaging systems, including hardware and software, and recent literature examples of 3D organotypic culture models employing this technology for drug discovery and toxicology screening. PMID:26608110

  17. Modern Natural Products Drug Discovery and its Relevance to Biodiversity Conservation†

    PubMed Central

    Kingston, David G. I.

    2010-01-01

    Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery, but maintaining their continued eminence as source compounds is challenging in the face of the changing face of the pharmaceutical industry and the changing nature of biodiversity prospecting brought about by the Convention of Biodiversity. This review provides an overview of some of these challenges, and suggests ways in which they can be addressed so that natural products research can remain a viable and productive route to drug discovery. Results from International Cooperative Biodiversity Groups (ICBGs) working in Madagascar, Panama, and Suriname are used as examples of what can be achieved when biodiversity conservation is linked to drug discovery. PMID:21138324

  18. Can Functional Magnetic Resonance Imaging Improve Success Rates in CNS Drug Discovery?

    PubMed Central

    Borsook, David; Hargreaves, Richard; Becerra, Lino

    2011-01-01

    Introduction The bar for developing new treatments for CNS disease is getting progressively higher and fewer novel mechanisms are being discovered, validated and developed. The high costs of drug discovery necessitate early decisions to ensure the best molecules and hypotheses are tested in expensive late stage clinical trials. The discovery of brain imaging biomarkers that can bridge preclinical to clinical CNS drug discovery and provide a ‘language of translation’ affords the opportunity to improve the objectivity of decision-making. Areas Covered This review discusses the benefits, challenges and potential issues of using a science based biomarker strategy to change the paradigm of CNS drug development and increase success rates in the discovery of new medicines. The authors have summarized PubMed and Google Scholar based publication searches to identify recent advances in functional, structural and chemical brain imaging and have discussed how these techniques may be useful in defining CNS disease state and drug effects during drug development. Expert opinion The use of novel brain imaging biomarkers holds the bold promise of making neuroscience drug discovery smarter by increasing the objectivity of decision making thereby improving the probability of success of identifying useful drugs to treat CNS diseases. Functional imaging holds the promise to: (1) define pharmacodynamic markers as an index of target engagement (2) improve translational medicine paradigms to predict efficacy; (3) evaluate CNS efficacy and safety based on brain activation; (4) determine brain activity drug dose-response relationships and (5) provide an objective evaluation of symptom response and disease modification. PMID:21765857

  19. Renal Safety Pharmacology in Drug Discovery and Development.

    PubMed

    Benjamin, Amanda; Nogueira da Costa, Andre; Delaunois, Annie; Rosseels, Marie-Luce; Valentin, Jean-Pierre

    2015-01-01

    The kidney is a complex excretory organ playing a crucial role in various physiological processes such as fluid and electrolyte balance, control of blood pressure, removal of waste products, and drug disposition. Drug-induced kidney injury (DIKI) remains a significant cause of candidate drug attrition during drug development. However, the incidence of renal toxicities in preclinical studies is low, and the mechanisms by which drugs induce kidney injury are still poorly understood. Although some in vitro investigational tools have been developed, the in vivo assessment of renal function remains the most widely used methodology to identify DIKI. Stand-alone safety pharmacology studies usually include assessment of glomerular and hemodynamic function, coupled with urine and plasma analyses. However, as renal function is not part of the ICH S7A core battery, such studies are not routinely conducted by pharmaceutical companies. The most common approach consists in integrating renal/urinary measurements in repeat-dose toxicity studies. In addition to the standard analyses and histopathological examination of kidneys, novel promising urinary biomarkers have emerged over the last decade, offering greater sensitivity and specificity than traditional renal parameters. Seven of these biomarkers have been qualified by regulatory agencies for use in rat toxicity studies. PMID:26091646

  20. Natural products and drug discovery: a survey of stakeholders in industry and academia

    PubMed Central

    Amirkia, Vafa; Heinrich, Michael

    2015-01-01

    Context: In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics. Aim: We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia. Method: We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia. Results: One recurrent theme is the dissonance between the perceived high potential of NP as drug leads among individuals and the survey participants' assessment of the overall industry and/or company level strategies and their success. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents. Surprisingly, many industry contacts were highly critical to prevalent company and industry-wide drug discovery strategies indicating a high level of dissatisfaction within the industry. Conclusions: These findings support the notion that there is an increasing gap in perception between the effectiveness of well established, commercially widespread drug discovery strategies between those working in industry and academic experts. This research seeks to shed light on this gap and aid in furthering natural product discovery endeavors through an analysis of current bottlenecks in industry drug discovery programmes. PMID:26578954

  1. Drug discovery in paediatric oncology: roadblocks to progress

    PubMed Central

    Adamson, Peter C.; Houghton, Peter J.; Perilongo, Giorgio; Pritchard-Jones, Kathy

    2015-01-01

    Approval of new cancer drugs for paediatric patients generally occurs after their development and approval for treating adult cancers. As most drug development occurs in the industry setting, the relatively small market of paediatric oncology does not provide the financial incentives for companies to actively pursue paediatric oncology solutions. Indeed, between 1948 and January 2003 the FDA approved 120 new cancer drugs, of which only 30 have been used in children. This slow rate of development must be addressed in a meaningful way if we are to make progress in the most pressing settings in childhood cancer. In this Viewpoint article, the key opinion leaders in the field weigh in and offer practical advice on how to address this issue. PMID:25223555

  2. Computational biology in anti-tuberculosis drug discovery.

    PubMed

    Murphy, Dennis J; Brown, James R

    2009-06-01

    The resurgence of drug resistant tuberculosis (TB) is a major global healthcare problem. Mycobacterium tuberculosis (MTB), TB's causative agent, evades the host immune system and drug regimes by entering prolonged periods of nonproliferation or dormancy. The identification of genes essential to the bacterium in its dormancy phase infections is a key strategy in the development of new anti-TB therapeutics. The rapid expansion of TB-related genomic data sources including DNA sequences, transcriptomic and proteomic profiles, and genome-wide essentiality data, present considerable opportunities to apply advanced computational analyses to predict potential drug targets. However, the translation of in silico predictions to effective clinical therapies remains a significant challenge. PMID:19519485

  3. Experimental Models of Anxiety for Drug Discovery and Brain Research.

    PubMed

    Hart, Peter C; Bergner, Carisa L; Smolinsky, Amanda N; Dufour, Brett D; Egan, Rupert J; LaPorte, Justin L; Kalueff, Allan V

    2016-01-01

    Animal models have been vital to recent advances in experimental neuroscience, including the modeling of common human brain disorders such as anxiety, depression, and schizophrenia. As mice express robust anxiety-like behaviors when exposed to stressors (e.g., novelty, bright light, or social confrontation), these phenotypes have clear utility in testing the effects of psychotropic drugs. Of specific interest is the extent to which mouse models can be used for the screening of new anxiolytic drugs and verification of their possible applications in humans. To address this problem, the present chapter will review different experimental models of mouse anxiety and discuss their utility for testing anxiolytic and anxiogenic drugs. Detailed protocols will be provided for these paradigms, and possible confounds will be addressed accordingly. PMID:27150096

  4. Antimalarial Drug Discovery: Approaches and Progress towards New Medicines

    PubMed Central

    Flannery, Erika L.; Chatterjee, Arnab K.; Winzeler, Elizabeth A.

    2014-01-01

    Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next generation medicines, public-private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite lifecycle. Here, we review the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing. PMID:24217412

  5. Mechanistic systems modeling to guide drug discovery and development

    PubMed Central

    Schmidt, Brian J.; Papin, Jason A.; Musante, Cynthia J.

    2013-01-01

    A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. PMID:22999913

  6. Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery

    PubMed Central

    Lee, Wen Hwa

    2015-01-01

    There is a scarcity of novel treatments to address many unmet medical needs. Industry and academia are finally coming to terms with the fact that the prevalent models and incentives for innovation in early stage drug discovery are failing to promote progress quickly enough. Here we will examine how an open model of precompetitive public–private research partnership is enabling efficient derisking and acceleration in the early stages of drug discovery, whilst also widening the range of communities participating in the process, such as patient and disease foundations. PMID:26042736

  7. Killing the hypnozoite – drug discovery approaches to prevent relapse in Plasmodium vivax

    PubMed Central

    Campo, Brice; Vandal, Omar; Wesche, David L.; Burrows, Jeremy N.

    2015-01-01

    The eradication of malaria will only be possible if effective, well-tolerated medicines kill hypnozoites in vivax and ovale malaria, and thus prevent relapses in patients. Despite progress in the 8-aminoquinoline series, with tafenoquine in Phase III showing clear benefits over primaquine, the drug discovery challenge to identify hypnozoiticidal or hypnozoite-activating compounds has been hampered by the dearth of biological tools and assays, which in turn has been limited by the immense scientific and logistical challenges associated with accessing relevant human tissue and sporozoites. This review summarises the existing drug discovery series and approaches concerning the goal to block relapse. PMID:25891812

  8. Alkaloids from marine invertebrates as important leads for anticancer drugs discovery and development.

    PubMed

    Imperatore, Concetta; Aiello, Anna; D'Aniello, Filomena; Senese, Maria; Menna, Marialuisa

    2014-01-01

    The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery. PMID:25490431

  9. Laboratory informatics tools integration strategies for drug discovery: integration of LIMS, ELN, CDS, and SDMS.

    PubMed

    Machina, Hari K; Wild, David J

    2013-04-01

    There are technologies on the horizon that could dramatically change how informatics organizations design, develop, deliver, and support applications and data infrastructures to deliver maximum value to drug discovery organizations. Effective integration of data and laboratory informatics tools promises the ability of organizations to make better informed decisions about resource allocation during the drug discovery and development process and for more informed decisions to be made with respect to the market opportunity for compounds. We propose in this article a new integration model called ELN-centric laboratory informatics tools integration. PMID:22895535

  10. Applications of (19)F-NMR in Fragment-Based Drug Discovery.

    PubMed

    Norton, Raymond S; Leung, Eleanor W W; Chandrashekaran, Indu R; MacRaild, Christopher A

    2016-01-01

    (19)F-NMR has proved to be a valuable tool in fragment-based drug discovery. Its applications include screening libraries of fluorinated fragments, assessing competition among elaborated fragments and identifying the binding poses of promising hits. By observing fluorine in both the ligand and the target protein, useful information can be obtained on not only the binding pose but also the dynamics of ligand-protein interactions. These applications of (19)F-NMR will be illustrated in this review with studies from our fragment-based drug discovery campaigns against protein targets in parasitic and infectious diseases. PMID:27438818

  11. [Drug safety--from patients' perspective].

    PubMed

    Kitazawa, Kyoko

    2011-01-01

    Patients expect drugs are 100% effective and safe. Unfortunately, however, most drugs are not. Continuous efforts by healthcare professionals and industry should be made to maximize efficacy and safety. Here, four challenges are shown from a viewpoint of laypersons. 1) Develop better drugs: Continuous efforts to develop drugs for 'neglected' diseases should be enhanced to meet unmet medical needs. 2) Deliver right drugs: Medication errors caused by similar names and shapes have been repeatedly reported. Communication with patients and their families may be helpful to decrease errors. 3) Improve the quality of drug information: How health professionals provide drug information to patients should be routinely monitored to improve the quality. Rephrasing to plain expressions may sometimes be useful for better communication. 4) Promote personalized medicine: Each patient wants to know whether this drug would work to him/herself as well as statistical data. Pharmacogenomics and pharmacokinetics/pharmacodynamics (PK/PD) research should be encouraged in order to develop personalized medicine. PMID:21628972

  12. Novel drugs against tuberculosis: a clinician's perspective.

    PubMed

    Olaru, Ioana Diana; von Groote-Bidlingmaier, Florian; Heyckendorf, Jan; Yew, Wing Wai; Lange, Christoph; Chang, Kwok Chiu

    2015-04-01

    The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. PMID:25431273

  13. Inflammation in atherosclerosis: new opportunities for drug discovery.

    PubMed

    Meng, Charles Q

    2005-01-01

    Many lines of evidence indicate that inflammation is the ultimate cause of atherosclerosis; high cholesterol levels cause atherosclerosis through mechanism of inflammation. Drugs designed to address inflammatory aspects of atherosclerosis will likely be more effective than current therapies in treating and preventing coronary artery disease. PMID:15638790

  14. Computational Discovery of Transcription Factors Associated With Drug Response

    PubMed Central

    Hanson, Casey; Cairns, Junmei; Wang, Liewei; Sinha, Saurabh

    2015-01-01

    This study integrates gene expression, genotype, and drug response data in lymphoblastoid cell lines with transcription factor (TF) binding sites from ENCODE, in a novel methodology that elucidates regulatory contexts associated with cytotoxicity. The method, GENMi, postulates that SNPs within TF binding sites putatively modulate its regulatory activity, and the resulting variation in gene expression leads to variation in drug response. Analysis of 161 TFs and 24 treatments revealed 334 significantly associated TF-treatment pairs. Investigation of 20 selected pairs yielded literature support for 13 of these associations, often from studies where perturbation of the TF’s expression changes drug response. Experimental validation of significant GENMi associations in taxanes and anthracyclines across two triple negative breast cancer cell lines corroborates our findings. The method is shown to be more sensitive than an alternative, GWAS-based approach that does not use gene expression. These results demonstrate GENMi’s utility in identifying TFs that influence drug response and provide a number of candidates for further testing. PMID:26503816

  15. New natural products as new leads for antibacterial drug discovery.

    PubMed

    Brown, Dean G; Lister, Troy; May-Dracka, Tricia L

    2014-01-15

    Natural products have been a rich source of antibacterial drugs for many decades, but investments in this area have declined over the past two decades. The purpose of this review article is to provide a recent survey of new natural product classes and the mechanisms by which they work. PMID:24388805

  16. Botanical-drug interactions: a scientific perspective.

    PubMed

    de Lima Toccafondo Vieira, Manuela; Huang, Shiew-Mei

    2012-09-01

    There is a continued predisposition of concurrent use of drugs and botanical products. A general lack of knowledge of the interaction potential together with an under-reporting of botanical use poses a challenge for the health care providers and a safety concern for patients. Botanical-drug interactions increase the patient risk, especially with regard to drugs with a narrow therapeutic index (e.g., warfarin, cyclosporine, and digoxin). Examples of case reports and clinical studies evaluating botanical-drug interactions of commonly used botanicals in the US are presented. The potential pharmacokinetic and pharmacodynamic bases of such interactions are discussed, as well as the challenges associated with the interpretation of the available data and prediction of botanical-drug interactions. Recent FDA experiences with botanical products and interactions including labeling implications as a risk management strategy are highlighted. PMID:22864989

  17. Shape shifting leads to small molecule allosteric drug discovery

    PubMed Central

    Lawrence, Sarah H.; Ramirez, Ursula D.; Tang, Lei; Fazliyev, Farit; Kundrat, Lenka; Markham, George D.; Jaffe, Eileen K.

    2009-01-01

    SUMMARY Enzymes that regulate their activity by modulating an equilibrium of alternate, non-additive, functionally distinct oligomeric assemblies (morpheeins) define a novel mode of allostery (Jaffe, TiBS 30:490-7, 2005). The oligomeric equilibrium for porphobilinogen synthase (PBGS) consists of high-activity octamers, low-activity hexamers, and two dimer conformations. A phylogenetically diverse allosteric site specific to hexamers is proposed as an inhibitor binding site. Inhibitor binding is predicted to draw the oligomeric equilibrium toward the low-activity hexamer. In silico docking enriched a selection from a small molecule library for compounds predicted to bind to this allosteric site. In vitro testing of selected compounds identified one compound whose inhibition mechanism is species-specific conversion of PBGS octamers to hexamers. We propose that this novel strategy for inhibitor discovery can be applied to other proteins that use the morpheein model for allosteric regulation. PMID:18559269

  18. Sports drug testing--an analyst's perspective.

    PubMed

    Trout, Graham J; Kazlauskas, Rymantas

    2004-01-10

    Sport plays a major role in the lives of many people, both for active participation and as entertainment. Sport is now a huge nationally and internationally based industry. The desire to win has led some athletes to resort to the use of performance enhancing drugs. With huge financial rewards now available in some sports the pressure to excel has grown. Some have argued that drug use should be given free rein, however most people are of the view that it is athletic prowess that should be applauded not the efficacy of various performance enhancing drugs. Apart from the obvious aspects of equality and fair play, the use of drugs is associated with significant health risks. In the 1960's the use of stimulants in sports such as cycling led to the death of at least one cyclist. Since 1968 the International Olympic Committee (IOC) has required all Olympic Games' host cities to provide laboratory facilities for the analysis and detection of performance enhancing drugs. There are now 29 IOC accredited laboratories throughout the world that routinely test samples from athletes for the presence of such drugs. The purpose of this tutorial review is to give an overview of drug testing procedures, including those that were used at the last summer Olympic Games in Sydney 2000, and the incorporation of the latest developments in analytical chemistry technology in the drug testing process. More recently, developments in biotechnology mean that the use of whole new classes of drugs are banned in sport, often requiring new methodologies and techniques for their analysis. The contest between those who wish to cheat and those who wish to maintain fair play in sport is an ongoing one. PMID:14737504

  19. Scoring functions for fragment-based drug discovery.

    PubMed

    Wang, Jui-Chih; Lin, Jung-Hsin

    2015-01-01

    Fragment-based drug design represents a challenge for computational drug design because almost inevitably fragments will be weak binders to the biomolecular targets of a specific disease, and the performances of the scoring functions for weak binders are usually poorer than those for the stronger binders. This protocol describes how to predict the binding modes and binding affinities of fragments towards their binding partner with our refined AutoDock scoring function incorporating a quantum chemical charge model, namely, the restrained electrostatic potential (RESP) model. This scoring function was calibrated by robust regression analysis and has been demonstrated to perform well for general classes of protein-ligand interactions and for weak binders (with root-mean square of error of about 2.1 kcal/mol). PMID:25709036

  20. Beyond Membrane Protein Structure: Drug Discovery, Dynamics and Difficulties.

    PubMed

    Biggin, Philip C; Aldeghi, Matteo; Bodkin, Michael J; Heifetz, Alexander

    2016-01-01

    Most of the previous content of this book has focused on obtaining the structures of membrane proteins. In this chapter we explore how those structures can be further used in two key ways. The first is their use in structure based drug design (SBDD) and the second is how they can be used to extend our understanding of their functional activity via the use of molecular dynamics. Both aspects now heavily rely on computations. This area is vast, and alas, too large to consider in depth in a single book chapter. Thus where appropriate we have referred the reader to recent reviews for deeper assessment of the field. We discuss progress via the use of examples from two main drug target areas; G-protein coupled receptors (GPCRs) and ion channels. We end with a discussion of some of the main challenges in the area. PMID:27553242

  1. Hydrophobicity – Shake Flasks, Protein Folding and Drug Discovery

    PubMed Central

    Sarkar, Aurijit; Kellogg, Glen E.

    2009-01-01

    Hydrophobic interactions are some of the most important interactions in nature. They are the primary driving force in a number of phenomena. This is mostly an entropic effect and can account for a number of biophysical events such as protein-protein or protein-ligand binding that are of immense importance in drug design. The earliest studies on this phenomenon can be dated back to the end of the 19th century when Meyer and Overton independently correlated the hydrophobic nature of gases to their anesthetic potency. Since then, significant progress has been made in this realm of science. This review briefly traces the history of hydrophobicity research along with the theoretical estimation of partition coefficients. Finally, the application of hydrophobicity estimation methods in the field of drug design and protein folding is discussed. PMID:19929828

  2. Cardiac models in drug discovery and development: a review.

    PubMed

    Amanfu, Robert K; Saucerman, Jeffrey J

    2011-01-01

    Cardiovascular diseases are among the leading causes of death in the developed world. Developing novel therapies for diseases like heart failure is crucial, but this is hampered by the high attrition rate in drug development. The withdrawal of drugs at the final hurdle of approval is mostly because of their unpredictable effects on normal cardiac rhythm. The advent of cardiac computational modeling in the last 5 decades has aided the understanding of heart function significantly. Recently, these models increasingly have been applied toward designing and understanding therapies for cardiac disease. This article will discuss how cellular models of electrophysiology, cell signaling, and metabolism have been used to investigate pharmacologic therapies for cardiac diseases including arrhythmia, ischemia, and heart failure. PMID:22196160

  3. ROR nuclear receptors: structures, related diseases, and drug discovery

    PubMed Central

    Zhang, Yan; Luo, Xiao-yu; Wu, Dong-hai; Xu, Yong

    2015-01-01

    Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs. PMID:25500868

  4. Structure-based drug discovery of carbonic anhydrase inhibitors.

    PubMed

    Supuran, Claudiu T

    2012-12-01

    Inhibition of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1) has pharmacologic applications in the field of anti-glaucoma, anti-convulsant and anti-cancer agents. But recently, it has also emerged that these enzymes have the potential for designing anti-infective drugs (anti-fungal and anti-bacterial agents) with a novel mechanism of action. Sulphonamides and their isosteres (sulphamates/sulphamides) constitute the main class of CA inhibitors (CAIs), which bind to the metal ion from the enzyme active site. Recently, the dithiocarbamates (DTCs), possessing a similar mechanism of action, were reported as a new class of inhibitors. These types of CAIs will be discussed in detail in this review. Novel drug design strategies have been reported ultimately based on the tail approach for obtaining sulphonamides/DTCs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Most of the promising data have been obtained by combining x-ray crystallography of enzyme-inhibitor adducts with novel synthetic approaches for generating chemical diversity. Whereas sulphonamide - NO donating hybrid drugs were reported as effective anti-glaucoma agents, most of the interesting new inhibitors were designed for inhibiting specifically the tumour-associated isoforms CA IX and XII, validated targets for imaging and treatment of hypoxic tumours. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the DTC and carboxylate types, will be also reviewed. PMID:22468747

  5. Stem cells: a model for screening, discovery and development of drugs

    PubMed Central

    Kitambi, Satish Srinivas; Chandrasekar, Gayathri

    2011-01-01

    The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson’s disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed. PMID:24198530

  6. Perspective: Dendrimer drugs for infection and inflammation.

    PubMed

    Shaunak, Sunil

    2015-12-18

    Biologists are dissecting complex biological pathways at breath taking speed. It is opening up new opportunities for the therapeutic evaluation of novel dendrimer drugs. This review focuses on studies of small dendrimers decorated with sulfate, phosphonate, N-acetyl-cysteine, glucosamine and mannose in animal model studies of infection and inflammation. It highlights those animal model studies which have demonstrated the most promising dendrimer drug constructs as potential new medicines. The issues relating to their analytical chemistry that are slowing the progress of dendrimer drugs into the clinic are highlighted. It should be possible to solve these with additional analytical expertise because it is small dendrimers with only 16-32 peripheral groups that make for the best infection and inflammation related medicines. Public-private partnerships are now needed to progress these dendrimer drugs into proof-of-concept clinical trials. PMID:26168733

  7. Drug misuse in sport: a historical perspective.

    PubMed

    Gerrard, David

    2015-12-01

    This editorial draws comparisons between the recent revelations of drug misuse in Russian sport, and the State-sponsored programme of the former German Democratic Republic. While 50 years separates these two regimes, there are commonalities. The history of major incidents involving drug abuse by serious national players in sport suggests a 20-year cycle, with the GDR, China and now Russia employing similar strategies. These events underscore the value placed upon international sporting success by politicians. PMID:26913904

  8. Drug discovery and development for ageing: opportunities and challenges

    PubMed Central

    Evans, William J.

    2011-01-01

    The prevention and treatment of late-life dysfunction are the goals of most geriatricians and should be the primary target for discovery and development of new medicines for elderly people. However, the development of new medicines for elderly people will face a number of challenges that are not seen for other patient populations. The burdens of multiple chronic diseases, low physiological reserve and polypharmacy must result in new clinical trials in frail older people with a high expectation of safety and efficacy. The etiology of functional limitations in elderly people is complex and often ascribed to conditions that escape the traditional definition of disease. While our society urgently needs new treatments that can reduce the burden of physical decline among older persons, guidelines on how these treatments should be developed and tested are currently lacking, in part because a consensus has not yet been achieved regarding the identifiable target diseases. New potential indications included sarcopaenia, anorexia of ageing, frailty, mobility disability and reduced functional capacity secondary to hospitalization. The challenges to conducting clinical trials in the elderly should not offset the great opportunity for the development of new medicines to prevent or reverse age-associated changes in body composition and poor functional capacity in the elderly. PMID:21115538

  9. A High-Throughput Screen for Antibiotic Drug Discovery

    PubMed Central

    Scanlon, Thomas C.; Dostal, Sarah M.; Griswold, Karl E.

    2014-01-01

    We describe an ultra-high-throughput screening platform enabling discovery and/or engineering of natural product antibiotics. The methodology involves creation of hydrogel-in-oil emulsions in which recombinant microorganisms are co-emulsified with bacterial pathogens; antibiotic activity is assayed by use of a fluorescent viability dye. We have successfully utilized both bulk emulsification and microfluidic technology for the generation of hydrogel microdroplets that are size-compatible with conventional flow cytometry. Hydrogel droplets are ~25 pL in volume, and can be synthesized and sorted at rates exceeding 3,000 drops/s. Using this technique, we have achieved screening throughputs exceeding 5 million clones/day. Proof-of-concept experiments demonstrate efficient selection of antibiotic-secreting yeast from a vast excess of negative controls. In addition, we have successfully used this technique to screen a metagenomic library for secreted antibiotics that kill the human pathogen Staphylococcus aureus. Our results establish the practical utility of the screening platform, and we anticipate that the accessible nature of our methods will enable others seeking to identify and engineer the next generation of antibacterial biomolecules. PMID:23955804

  10. Microtubule-stabilizing agents: New drug discovery and cancer therapy.

    PubMed

    Zhao, Ying; Mu, Xin; Du, Guanhua

    2016-06-01

    Microtubule-stabilizing agents (MSAs) have been highly successful in the treatment of cancer in the past 20years. To date, three classes of MSAs have entered the clinical trial stage or have been approved for clinical anticancer chemotherapy, and more than 10 classes of novel structural MSAs have been derived from natural resources. The microtubule typically contains two MSA-binding sites: the taxoid site and the laulimalide/peloruside site. All defined MSAs are known to bind at either of these sites, with subtle but significant differences. MSAs with different binding sites may produce a synergistic effect. Although having been extensively applied in the clinical setting, paclitaxel and other approved MSAs still pose many challenges such as multidrug resistance, low bioavailability, poor solubility, high toxicity, and low passage through the blood-brain barrier. A variety of studies focus on the structure-activity relationship in order to improve the pharmaceutical properties of these agents. Here, the mechanisms of action, advancements in pharmacological research, and clinical developments of defined MSAs during the past decade are discussed. The latest discovered MSAs are also briefly introduced in this review. The increasing number of natural MSAs indicates the potential discovery of more novel, natural MSAs with different structural bases, which will further promote the development of anticancer chemotherapy. PMID:26706241

  11. COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

    PubMed Central

    Kapetanovic, I.M.

    2008-01-01

    It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

  12. Precision multidimensional assay for high-throughput microRNA drug discovery

    PubMed Central

    Haefliger, Benjamin; Prochazka, Laura; Angelici, Bartolomeo; Benenson, Yaakov

    2016-01-01

    Development of drug discovery assays that combine high content with throughput is challenging. Information-processing gene networks can address this challenge by integrating multiple potential targets of drug candidates' activities into a small number of informative readouts, reporting simultaneously on specific and non-specific effects. Here we show a family of networks implementing this concept in a cell-based drug discovery assay for miRNA drug targets. The networks comprise multiple modules reporting on specific effects towards an intended miRNA target, together with non-specific effects on gene expression, off-target miRNAs and RNA interference pathway. We validate the assays using known perturbations of on- and off-target miRNAs, and evaluate an ∼700 compound library in an automated screen with a follow-up on specific and non-specific hits. We further customize and validate assays for additional drug targets and non-specific inputs. Our study offers a novel framework for precision drug discovery assays applicable to diverse target families. PMID:26880188

  13. Precision multidimensional assay for high-throughput microRNA drug discovery.

    PubMed

    Haefliger, Benjamin; Prochazka, Laura; Angelici, Bartolomeo; Benenson, Yaakov

    2016-01-01

    Development of drug discovery assays that combine high content with throughput is challenging. Information-processing gene networks can address this challenge by integrating multiple potential targets of drug candidates' activities into a small number of informative readouts, reporting simultaneously on specific and non-specific effects. Here we show a family of networks implementing this concept in a cell-based drug discovery assay for miRNA drug targets. The networks comprise multiple modules reporting on specific effects towards an intended miRNA target, together with non-specific effects on gene expression, off-target miRNAs and RNA interference pathway. We validate the assays using known perturbations of on- and off-target miRNAs, and evaluate an ∼700 compound library in an automated screen with a follow-up on specific and non-specific hits. We further customize and validate assays for additional drug targets and non-specific inputs. Our study offers a novel framework for precision drug discovery assays applicable to diverse target families. PMID:26880188

  14. Disciplined approach to drug discovery and early development.

    PubMed

    Plenge, Robert M

    2016-07-27

    Our modern health care system demands therapeutic interventions that improve the lives of patients. Unfortunately, decreased productivity in therapeutics research and development (R&D) has driven drug costs up while delivering insufficient value to patients. Here, I discuss a model of translational medicine that connects four components of the early R&D pipeline-causal human biology, therapeutic modality, biomarkers of target modulation, and proof-of-concept clinical trials. Whereas the individual components of this model are not new, technological advances and a disciplined approach to integrating all four areas offer hope for improving R&D productivity. PMID:27464747

  15. [Large scale quantum chemical calculation for drug discovery].

    PubMed

    Kitaura, Kazuo

    2011-01-01

    Due to the increase in computer power and the development of computational methods, it becomes possible to perform quantum mechanical calculations of very large molecules such as proteins that were previously exclusively treated with classical force field methods. We have developed the fragment molecular orbital (FMO) method aimed at biomolecular applications. One of the important applications of the method is in structure-based drug design because it provides accurate descriptions of various non-bonded interactions between a protein and its ligand. In this article, the FMO method will be described as well as its applications to the analysis of protein-ligand binding. PMID:21804319

  16. The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential.

    PubMed

    Janero, David R

    2014-08-01

    Technology often serves as a handmaiden and catalyst of invention. The discovery of safe, effective medications depends critically upon experimental approaches capable of providing high-impact information on the biological effects of drug candidates early in the discovery pipeline. This information can enable reliable lead identification, pharmacological compound differentiation and successful translation of research output into clinically useful therapeutics. The shallow preclinical profiling of candidate compounds promulgates a minimalistic understanding of their biological effects and undermines the level of value creation necessary for finding quality leads worth moving forward within the development pipeline with efficiency and prognostic reliability sufficient to help remediate the current pharma-industry productivity drought. Three specific technologies discussed herein, in addition to experimental areas intimately associated with contemporary drug discovery, appear to hold particular promise for strengthening the preclinical valuation of drug candidates by deepening lead characterization. These are: i) hydrogen-deuterium exchange mass spectrometry for characterizing structural and ligand-interaction dynamics of disease-relevant proteins; ii) activity-based chemoproteomics for profiling the functional diversity of mammalian proteomes; and iii) nuclease-mediated precision gene editing for developing more translatable cellular and in vivo models of human diseases. When applied in an informed manner congruent with the clinical understanding of disease processes, technologies such as these that span levels of biological organization can serve as valuable enablers of drug discovery and potentially contribute to reducing the current, unacceptably high rates of compound clinical failure. PMID:24965547

  17. CRIMALDDI: a prioritized research agenda to expedite the discovery of new anti-malarial drugs

    PubMed Central

    2013-01-01

    The CRIMALDDI Consortium has been a three-year project funded by the EU Framework Seven Programme. It aimed to develop a prioritized set of recommendations to speed up anti-malarial drug discovery research and contribute to the setting of the global research agenda. It has attempted to align thinking on the high priority issues and then to develop action plans and strategies to address these issues. Through a series of facilitated and interactive workshops, it has concluded that these priorities can be grouped under five key themes: attacking artemisinin resistance; creating and sharing community resources; delivering enabling technologies; exploiting high throughput screening hits quickly; and, identifying novel targets. Recommendations have been prioritized into one of four levels: quick wins; removing key roadblocks to future progress; speeding-up drug discovery; and, nice to have (but not essential). Use of this prioritization allows efforts and resources to be focused on the lines of work that will contribute most to expediting anti-malarial drug discovery. Estimates of the time and finances required to implement the recommendations have also been made, along with indications of when recommendations within each theme will make an impact. All of this has been collected into an indicative roadmap that, it is hoped, will guide decisions about the direction and focus of European anti-malarial drug discovery research and contribute to the setting of the global research agenda. PMID:24191947

  18. Four Lessons from Global Health Drug Discovery: Medicine for an Ailing Industry?

    PubMed Central

    2012-01-01

    In recent years, the pharmaceutical industry has faced many challenges to its business model, undergoing tremendous change and turmoil to survive. Are there any lessons to be drawn from drug discovery focused on Global Health, where there is little market incentive? PMID:24900531

  19. Diversity-oriented synthetic strategies applied to cancer chemical biology and drug discovery.

    PubMed

    Collins, Ian; Jones, Alan M

    2014-01-01

    How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery. PMID:25350364

  20. Discovery of the target for immunomodulatory drugs (IMiDs).

    PubMed

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2016-05-01

    Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity. Recently, new thalidomide derivatives, called immunomodulatory drugs (IMiDs), have been developed by Celgene. Among them, lenalidomide (Len) and pomalidomide (Pom) were shown to exert strong therapeutic effects against MM. It was found that Len and Pom both bind CRBN-CRL4 and recruit neomorphic substrates (Ikaros and Aiolos). More recently it was reported that casein kinase 1a (Ck1a) was identified as a substrate for CRBN-CRL4 in the presence of Len, but not Pom. Ck1a breakdown explains why Len is specifically effective for myelodysplastic syndrome with 5q deletion. It is now proposed that binding of IMiDs to CRBN appears to alter the substrate specificity of CRBN-CRL4. In this review, we introduce recent findings on IMiDs. PMID:27263779

  1. Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

    PubMed Central

    Smithers, Cameron C.; Overduin, Michael

    2016-01-01

    Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies. PMID:27304967

  2. Approaches of targeting Rho GTPases in cancer drug discovery

    PubMed Central

    Lin, Yuan; Zheng, Yi

    2016-01-01

    Introduction Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. Areas covered This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. Expert opinion To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents. PMID:26087073

  3. Structural Mechanisms and Drug Discovery Prospects of Rho GTPases.

    PubMed

    Smithers, Cameron C; Overduin, Michael

    2016-01-01

    Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies. PMID:27304967

  4. MicroRNA in neurodegenerative drug discovery: the way forward?

    PubMed

    Campbell, Kristyn; Booth, Stephanie A

    2015-01-01

    Neurodegenerative diseases occur when neuronal cells in the brain or spinal cord progressively lose function and eventually die. Pathological analysis of these tissues reveals changes that include the loss of synapses, tangles of misfolded protein and immune cell activation, even during very early stages of disease well before debilitating clinical signs are apparent. This suggests that if neurodegeneration is treated early enough, drugs designed to delay the progress of these diseases by either repairing the early damage and loss of neurons, or protecting neuron functionality from further insult, may be efficacious. MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate gene expression. They are particularly numerous within neurons where many are expressed with high specificity, which suggests that they have important roles in the healthy brain. Indeed, miRNAs are essential for the post-mitotic survival of neurons, implying a crucial role in survival and neuroprotection. This has focused attention on exploring the use of miRNA-based drugs as a means to correct cellular abnormalities and maintain neuronal function in neurodegenerative diseases. These efforts are spurred on by the rapid progress to clinical trials for a number of miRNA-based therapies for other diseases such as cardiovascular diseases, fibrosis and cancer. PMID:25405898

  5. Screening applications in drug discovery based on microfluidic technology.

    PubMed

    Eribol, P; Uguz, A K; Ulgen, K O

    2016-01-01

    Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays. PMID:26865904

  6. Interactive perspective: drug development and FDA approval, 1938-2013.

    PubMed

    2015-02-01

    Interactive Perspective: Drug Development and FDA Approval, 1938-2013 (June 26, 2014;370:e39). The order of authors was incorrect; Dr. Darrow should have been listed first, and Dr. Kesselheim second. The article is correct at NEJM.org. PMID:25651270

  7. Current perspectives on intrathecal drug delivery

    PubMed Central

    Bottros, Michael M; Christo, Paul J

    2014-01-01

    Advances in intrathecal analgesia and intrathecal drug delivery systems have allowed for a range of medications to be used in the control of pain and spasticity. This technique allows for reduced medication doses that can decrease the side effects typically associated with oral or parenteral drug delivery. Recent expert panel consensus guidelines have provided care paths in the treatment of nociceptive, neuropathic, and mixed pain syndromes. While the data for pain relief, adverse effect reduction, and cost-effectiveness with cancer pain control are compelling, the evidence is less clear for noncancer pain, other than spasticity. Physicians should be aware of mechanical, pharmacological, surgical, and patient-specific complications, including possible granuloma formation. Newer intrathecal drug delivery systems may allow for better safety and quality of life outcomes. PMID:25395870

  8. Ultrafast laser processing of drug particles in water for pharmaceutical discovery

    NASA Astrophysics Data System (ADS)

    Ding, Weimeng; Sylvestre, Jean-Philippe; Bouvier, Emmanuelle; Leclair, Grégoire; Meunier, Michel

    2014-01-01

    The laser fragmentation technique has been extensively used to produce inorganic nanoparticles, but its practice on organic materials, especially on drugs, is less common. Here, we briefly review the recent advances in laser micro-/nanonization of organic materials and the rationale of using laser fragmentation for drug discovery. We present our case studies of two drug models: fenofibrate and naproxen. Both drugs were fragmented in water with femtosecond (fs) laser and characterized in terms of particle size distribution and physicochemical properties. Effects of fs laser fragmentation were also compared with nanosecond (ns) laser fragmentation and with conventional media milling technique. Fs laser was more suitable to produce sub-micron size drug particles than ns laser, but degradation of drugs after nanonization was also more pronounced than micronization. Physicochemical transformations such as oxidation, hydration and amorphisation might occur during the laser-material interactions. Laser nanonization showed improved dissolution kinetics, similar to media milling. Unlike the conventional milling techniques, laser fragmentation enabled the treatment of minute amount (as small as several milligrams) of drugs with high efficiency, thus is a useful tool for particle size reduction during the early phases of drug discovery.

  9. Isotope chemistry; a useful tool in the drug discovery arsenal.

    PubMed

    Elmore, Charles S; Bragg, Ryan A

    2015-01-15

    As Medicinal Chemists are responsible for the synthesis and optimization of compounds, they often provide intermediates for use by isotope chemistry. Nevertheless, there is generally an incomplete understanding of the critical factors involved in the labeling of compounds. The remit of an Isotope Chemistry group varies from company to company, but often includes the synthesis of compounds labeled with radioisotopes, especially H-3 and C-14 and occasionally I-125, and stable isotopes, especially H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prepare radiolabeled compounds by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chemistry has not been discussed recently and will be reviewed herein. PMID:25499878

  10. Pluripotent stem cells in disease modelling and drug discovery.

    PubMed

    Avior, Yishai; Sagi, Ido; Benvenisty, Nissim

    2016-03-01

    Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening. PMID:26818440

  11. Generation of BAC reporter cell lines for drug discovery.

    PubMed

    Kao, Betty R; McColl, Bradley; Vadolas, Jim

    2015-01-01

    Bacterial artificial chromosome (BAC) reporter cell lines are generated through stable transfection of a BAC reporter construct wherein the gene of interest is tagged with a reporter gene such as eGFP. The large capacity of BACs (up to 350 kb of genomic sequence) enables the inclusion of all regulatory elements that ensure appropriate regulation of the gene of interest. Furthermore, the reporter gene allows the expression of the gene of interest to be readily detected by flow cytometry. Cell lines can also be easily cultured for extended periods with minimal cost. These features of BAC reporter cell lines make them highly amenable for use in high-throughput screening of large drug libraries for compounds that induce the expression of the gene of interest. This chapter describes a method for generation of BAC reporter cell lines that are suitable as cellular assay systems in high-throughput screening. Briefly, this method involves (A) generation of cell clones stably transfected with a BAC reporter construct, (B) selection of "candidate" cell clones based on the responsiveness to known inducers, (C) confirmation of the integrity of the BAC reporter construct integrated within the candidate clones, and (D) assessment of the developmental regulation of the BAC reporter construct. As an example, we describe the generation of a BAC reporter cell line containing the human β-globin locus modified to express γ-globin as eGFP for use as a cellular reporter assay for screening of drugs that can reactivate expression of developmentally silenced γ-globin for the treatment of β-hemoglobin disorders. PMID:25239756

  12. New Perspectives on Drug Education/Prevention.

    PubMed

    Rosenbaum, Marsha

    2016-01-01

    In 2014, Oregon, Alaska, and the District of Columbia joined Colorado and Washington as voters approved initiatives to legally regulate and tax marijuana for adults. Other states, including California, are likely to follow in 2016. While none of these new laws allow sales to minors, there is widespread concern about the potential impact of these reforms on teenagers. Many worry that legalization will "send the wrong message," and increase access and availability, leading to an escalation in teenage use. This new social, political and cultural context presents a new challenge, as marijuana gradually becomes a normal part of the adult world, akin to alcohol. The movement toward legalization provides an opportunity to re-think our approach to teen drug education/prevention. This is the moment to examine current approaches, and devise innovative, pragmatic strategies for dealing with teens and marijuana (and other drug use). As we examine the issue of drug education/prevention in the context of legalization, we detail efforts that have been tried, and what is realistically possible to accomplish, with the health and safety of teenagers our highest priority. A reality-based approach advocates honest, science-based information; encourages moderation, if experimentation persists; promotes an understanding of the legal consequences and social context of drug use; emphasizes safety through personal responsibility and knowledge; and encourages the delay of experimentation with all intoxicating substances until adulthood. PMID:26799842

  13. Recent Perspectives in Ocular Drug Delivery

    PubMed Central

    Gaudana, Ripal; Jwala, J.; Boddu, Sai H. S.; Mitra, Ashim K.

    2015-01-01

    Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. PMID:18758924

  14. Anti dermatophytic therapy - Prospects for the discovery of new drugs from natural products

    PubMed Central

    Soares, Luciana Arantes; de Cássia Orlandi Sardi, Janaína; Gullo, Fernanda Patrícia; de Souza Pitangui, Nayla; Scorzoni, Liliana; Leite, Fernanda Sangalli; Giannini, Maria José Soares Mendes; Almeida, Ana Marisa Fusco

    2013-01-01

    Millions of people and animals suffer from superficial infections caused by a group of highly specialized filamentous fungi, the dermatophytes, which only infect keratinized structures. With the appearance of AIDS, the incidence of dermatophytosis has increased. Current drug therapy used for these infections is often toxic, long-term, and expensive and has limited effectiveness; therefore, the discovery of new anti dermatophytic compounds is a necessity. Natural products have been the most productive source for new drug development. This paper provides a brief review of the current literature regarding the presence of dermatophytes in immunocompromised patients, drug resistance to conventional treatments and new anti dermatophytic treatments. PMID:24688490

  15. Liquid-based three-dimensional tumor models for cancer research and drug discovery.

    PubMed

    Ham, Stephanie L; Joshi, Ramila; Thakuri, Pradip S; Tavana, Hossein

    2016-05-01

    Tumors are three-dimensional tissues where close contacts between cancer cells, intercellular interactions between cancer and stromal cells, adhesion of cancer cells to the extracellular matrix, and signaling of soluble factors modulate functions of cancer cells and their response to therapeutics. Three-dimensional cultures of cancer cells overcome limitations of traditionally used monolayer cultures and recreate essential characteristics of tumors such as spatial gradients of oxygen, growth factors, and metabolites and presence of necrotic, hypoxic, quiescent, and proliferative cells. As such, three-dimensional tumor models provide a valuable tool for cancer research and oncology drug discovery. Here, we describe different tumor models and primarily focus on a model known as tumor spheroid. We summarize different technologies of spheroid formation, and discuss the use of spheroids to address the influence of stromal fibroblasts and immune cells on cancer cells in tumor microenvironment, study cancer stem cells, and facilitate compound screening in the drug discovery process. We review major techniques for quantification of cellular responses to drugs and discuss challenges ahead to enable broad utility of tumor spheroids in research laboratories, integrate spheroid models into drug development and discovery pipeline, and use primary tumor cells for drug screening studies to realize personalized cancer treatment. PMID:27072562

  16. Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.

    PubMed

    Ishibashi, Daisuke; Nakagaki, Takehiro; Ishikawa, Takeshi; Atarashi, Ryuichiro; Watanabe, Ken; Cruz, Felipe A; Hamada, Tsuyoshi; Nishida, Noriyuki

    2016-07-01

    The accumulation of abnormal prion protein (PrP(Sc)) converted from the normal cellular isoform of PrP (PrP(C)) is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE) that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects. Among the candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrP(Sc) and protein-aggresomes in the prion-infected cells. The fragment molecular orbital calculation showed that the van der Waals interaction played a key role in PrP(C) binding as the intermolecular interaction mode. Furthermore, PrP(Sc) accumulation and microgliosis were significantly reduced in the brains of treated mice, suggesting that the drug candidates provided protection from prion disease, although further in vivo tests are needed to confirm these findings. This NUDE-based structure-based drug discovery for normal protein structures is likely useful for the development of drugs to treat other conformational disorders, such as Alzheimer's disease. PMID:27333028

  17. Virtualizing the p-ANAPL Library: A Step towards Drug Discovery from African Medicinal Plants

    PubMed Central

    Fotso, Ghislain W.; Andrae-Marobela, Kerstin; Bezabih, Merhatibeb; Ndom, Jean Claude; Ngadjui, Bonaventure T.; Ogundaini, Abiodun O.; Abegaz, Berhanu M.; Meva’a, Luc Mbaze

    2014-01-01

    Background Natural products play a key role in drug discovery programs, both serving as drugs and as templates for the synthesis of drugs, even though the quantities and availabilities of samples for screening are often limitted. Experimental approach A current collection of physical samples of > 500 compound derived from African medicinal plants aimed at screening for drug discovery has been made by donations from several researchers from across the continent to be directly available for drug discovery programs. A virtual library of 3D structures of compounds has been generated and Lipinski’s “Rule of Five” has been used to evaluate likely oral availability of the samples. Results A majority of the compound samples are made of flavonoids and about two thirds (2/3) are compliant to the “Rule of Five”. The pharmacological profiles of thirty six (36) selected compounds in the collection have been discussed. Conclusions and implications The p-ANAPL library is the largest physical collection of natural products derived from African medicinal plants directly available for screening purposes. The virtual library is also available and could be employed in virtual screening campaigns. PMID:24599120

  18. ChEMBL web services: streamlining access to drug discovery data and utilities

    PubMed Central

    Davies, Mark; Nowotka, Michał; Papadatos, George; Dedman, Nathan; Gaulton, Anna; Atkinson, Francis; Bellis, Louisa; Overington, John P.

    2015-01-01

    ChEMBL is now a well-established resource in the fields of drug discovery and medicinal chemistry research. The ChEMBL database curates and stores standardized bioactivity, molecule, target and drug data extracted from multiple sources, including the primary medicinal chemistry literature. Programmatic access to ChEMBL data has been improved by a recent update to the ChEMBL web services (version 2.0.x, https://www.ebi.ac.uk/chembl/api/data/docs), which exposes significantly more data from the underlying database and introduces new functionality. To complement the data-focused services, a utility service (version 1.0.x, https://www.ebi.ac.uk/chembl/api/utils/docs), which provides RESTful access to commonly used cheminformatics methods, has also been concurrently developed. The ChEMBL web services can be used together or independently to build applications and data processing workflows relevant to drug discovery and chemical biology. PMID:25883136

  19. Drug discovery management, small is still beautiful: Why a number of companies get it wrong.

    PubMed

    Knutsen, Lars J S

    2011-06-01

    This review provides an account of why more companies involved in drug discovery fail than succeed at releasing the creative energy of gifted scientists, whose invention of new drugs they rely upon to remain at the forefront of the biopharma industry. Initiatives aimed at improving output of new chemical entities often have the opposite effect from that intended and scientists become demotivated. Those with drive, vision and enthusiasm may move to smaller companies to rediscover the spirit of discovery. Some executives fail to understand the psyche of researchers; an applied understanding of the intrinsic motivation of scientists would improve research performance. Entities that focus on smaller autonomous units and sound ethical values will discover the most innovative and successful new drugs. PMID:21504798

  20. Professional translational research: a new hybrid paradigm in early drug discovery.

    PubMed

    Nussbaumer, Peter; Klebl, Bert

    2015-01-01

    While industry makes cuts to early drug discovery research, the demand for innovation in the pursuit of novel medicines continues to grow. Who should fill this gap? Academia clearly is a rich source of innovation but how can new basic research concepts find their way into industrial application? A new paradigm for early drug discovery involves professional translational research centers, which function as facilitators and translators at the academia-industry interface, harnessing the strengths of both worlds and leveraging the high innovation potential of academia by using the robustness and efficiency of industry. In this article, the authors discuss the set-up and essential requirements for the successful translation of new drug concepts. PMID:26420644

  1. Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis.

    PubMed

    Njogu, Peter M; Guantai, Eric M; Pavadai, Elumalai; Chibale, Kelly

    2016-01-01

    Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014). PMID:27622945

  2. Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.

    PubMed

    Hall, David R; Kozakov, Dima; Whitty, Adrian; Vajda, Sandor

    2015-11-01

    Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high-affinity, drug-like ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from a protein 3D structure, and how their strength, number, and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery. PMID:26538314

  3. G Protein-Coupled Receptors - Targets for Fragment-based Drug Discovery.

    PubMed

    Lawson, Alastair D G

    2015-01-01

    As the considerable technical challenges involved with generating crystal structures of G (guanine nucleotide- binding) protein-coupled receptors (GPCRs) are starting to be successfully addressed, opportunities to apply fragment-based drug discovery (FBDD) to this class of target are becoming a reality. GPCRs represent a large and important family of drug targets with considerable clinical and commercial interest. While their general seven transmembrane helix bundle structures are amenable to therapeutic intervention with small molecules, to date successful drugs have primarily been discovered using traditional competitive or function-based screening. With advances in biophysical screening techniques such as Surface Plasmon Resonance (SPR) and Target-Immobilised NMR Screening (TINS), being matched to developments in molecular dynamics simulations, virtual screening and stabilisation of biologically relevant conformations of GPCRs, structure-based approaches using fragment starting points are beginning to be applied to the discovery of new generations of small molecules. PMID:26126904

  4. Discovery

    ERIC Educational Resources Information Center

    de Mestre, Neville

    2010-01-01

    All common fractions can be written in decimal form. In this Discovery article, the author suggests that teachers ask their students to calculate the decimals by actually doing the divisions themselves, and later on they can use a calculator to check their answers. This article presents a lesson based on the research of Bolt (1982).

  5. Bioterrorism: a new frontier for drug discovery and development.

    PubMed

    Shailubhai, Kunwar

    2003-08-01

    Only a few years ago bioterrorism was considered a remote concern but today it has reached the forefront of the public imagination following recent terrorist attacks around the world. The disaster of September 11 2001, followed by anthrax letters sent via the US postal system, and now the renewed tension in the Middle East, have all brought the possibility of bioterrorism a little closer to reality. A number of biological agents could be used in a terrorist attack, including anthrax, botulinum, plague, smallpox, staphylococcal and streptococcal toxins, and the list of emerging pathogens is evolving rapidly. The serious diseases that these agents produce could cause considerable morbidity and mortality if used in a terrorist attack. This evolving threat presents the medical, public health and scientific communities with pressing challenges. The present research efforts in academia are primarily focused on the basic research on the pathogens that are considered to be bioweapons for terrorist attack. Thus, collaborative efforts between academic institutes, pharmaceutical industries and governmental agencies are warranted to translate basic research into drugs, vaccines and diagnostic tests. This review provides a brief overview of the threat from biological weapons and the current biodefense strategy to prevent and control outbreaks of diseases caused by intentional release of these bioweapons of mass destruction. PMID:12917773

  6. Characterizing Septum Inhibition in Mycobacterium tuberculosis for Novel Drug Discovery

    SciTech Connect

    Respicio,L.; Nair, P.; Huang, Q.; Anil, B.; Tracz, S.; Truglio, J.; Kisker, C.; Raleigh, D.; Ojima, I.; et al

    2008-01-01

    A temperature sensitive mutation in the cell division protein FtsZ was used in combination with transcriptional analysis to identify biomarkers for inhibition of septum formation. Crystallography and modeling revealed that the glycine for aspartate substitution at amino acid 210 was located in helix 8 of the protein, adjacent to the T7 synergy loop. To verify the molecular behavior of FtsZD210G, the in vitro activity and structural stability were evaluated as a function of temperature. These analyses confirmed that the FtsZD210G mutant had reduced GTPase and polymerization activity compared to wild-type FtsZ, and CD spectroscopy demonstrated that both FtsZD210G and wild-type FtsZ had similar structure and stability. Significantly, the FtsZD210G merodiploid strain of M. tuberculosis had compromised growth at 37 C, substantiating the suitability of FtsZD210G as a molecular tool for global analysis in response to improper FtsZ polymerization and septum inhibition. Advanced model-based bioinformatics and transcriptional mapping were used to identify high-content multiple features that provide biomarkers for the development of a rational drug screening platform for discovering novel chemotherapeutics that target cell division.

  7. Antibacterial drug discovery in the 21st century.

    PubMed

    Bush, K

    2004-11-01

    Antibacterial research over the past 50 years has been focused on meeting medical needs caused by infectious, life-threatening pathogens. In spite of the introduction of a variety of antibacterial agents in multiple unrelated drug classes, resistance continues to emerge. The pharmaceutical industry must respond to these clinical challenges by bringing forward a stream of new agents with antibacterial activity against resistant bacteria. Although the projected growth of the anti-infective area may not be as large as for some therapeutic areas, development advantages for these agents include their higher predictability for success, well-defined biomarkers, shorter clinical trials, and shorter duration of therapy leading to fewer long-term safety concerns. Anti-infectives are still attractive commercially, representing the third largest therapeutic area in terms of worldwide sales of 45 bn dollars, with growth predicted at least through 2010, particularly for the hospital-related products. Finally, companies that conduct anti-infective research demonstrate their social responsibility by developing agents to treat patients with acute and potentially fatal illnesses. PMID:15522035

  8. Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery.

    PubMed

    Merk, Alan; Bartesaghi, Alberto; Banerjee, Soojay; Falconieri, Veronica; Rao, Prashant; Davis, Mindy I; Pragani, Rajan; Boxer, Matthew B; Earl, Lesley A; Milne, Jacqueline L S; Subramaniam, Sriram

    2016-06-16

    Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic resolution structures for well-ordered protein complexes with sizes ≥ ∼200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 Å resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-Å- and 1.8-Å-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 Å resolution and (2) obtaining structures of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states. PMID:27238019

  9. Advances in MRSA drug discovery: where are we and where do we need to be?

    PubMed Central

    Kurosu, Michio; Siricilla, Shajila; Mitachi, Katsuhiko

    2013-01-01

    Introduction Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multi-drug-resistant (MDR) bacterial strains. Although, only a limited number of anti-MRSA drugs are available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, addition of several new antistaphylococcal drugs into clinical practice should broaden therapeutic options. Because MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts on discovery of lead compounds as well as development of alternative therapies and faster diagnostics to ensure effective antistaphylococcal therapy are required. Areas covered This article summarizes the FDA approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the mode of action of antistaphylococcal molecules and resistant mechanisms of some molecules are briefly discussed. Expert opinion The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for the infections by MRSA in the critically ill. This review article provides an update on antistaphylococcal drugs in clinical trials and antibacterial molecules effective against Gram-positive bacteria including MRSA. The structural and biological information of antibacterials summarized here are very useful for designing drug leads to develop into new anti-MRSA drugs. PMID:23829425

  10. Pollution from drug manufacturing: review and perspectives

    PubMed Central

    Larsson, D. G. Joakim

    2014-01-01

    As long ago as the sixteenth century, Paracelsus recognized that ‘the dose makes the poison’. Indeed, environmental concentrations of pharmaceuticals excreted by humans are limited, most importantly because a defined dose is given to just a fraction of the population. By contrast, recent studies have identified direct emission from drug manufacturing as a source of much higher environmental discharges that, in some cases, greatly exceed toxic threshold concentrations. Because production is concentrated in specific locations, the risks are not linked to usage patterns. Furthermore, as the drugs are not consumed, metabolism in the human body does not reduce concentrations. The environmental risks associated with manufacturing therefore comprise a different, wider set of pharmaceuticals compared with those associated with risks from excretion. Although pollution from manufacturing is less widespread, discharges that promote the development of drug-resistant microorganisms can still have global consequences. Risk management also differs between production and excretion in terms of accountability, incentive creation, legal opportunities, substitution possibilities and costs. Herein, I review studies about industrial emissions of pharmaceuticals and the effects associated with exposure to such effluents. I contrast environmental pollution due to manufacturing with that due to excretion in terms of their risks and management and highlight some recent initiatives. PMID:25405961

  11. In vitro model of mycobacteria and HIV-1 co-infection for drug discovery.

    PubMed

    Vijayakumar, Sudhamathi; Finney John, Sarah; Nusbaum, Rebecca J; Ferguson, Monique R; Cirillo, Jeffrey D; Olaleye, Omonike; Endsley, Janice J

    2013-12-01

    Tuberculosis (TB) has become a global health threat in the wake of the Human Immunodeficiency Virus (HIV) pandemic and is the leading cause of death in people with HIV/AIDS. Treatment of patients with Mycobacterium tuberculosis (Mtb)/HIV co-infection is complicated by drug interactions and toxicity that present huge challenges for clinical intervention. Discovery efforts to identify novel compounds with increased effectiveness and decreased drug-drug interactions against Mtb, HIV-1, or both, would be greatly aided by the use of a co-infection model for screening drug libraries. Currently, inhibitors of Mtb are screened independently in mycobacterial cell cultures or target based biochemical screens and less often in macrophages or peripheral blood leukocytes. Similarly, HIV-1 drugs are screened in vitro independently from anti-mycobacterial compounds. Here, we describe an in vitro model where primary human peripheral blood mononuclear cells or monocyte-derived macrophages are infected with Mycobacterium bovis BCG and HIV-1, and used to evaluate drug toxicity and activity in a co-infection setting. Our results with standard compounds (e.g. Azidothymidine, Rifampicin) demonstrate the utility of this in vitro model to evaluate drug effectiveness relevant to cellular toxicity, HIV-1 replication, and intracellular mycobacterial growth, through the use of ELISA, bacterial enumeration, and multi-variate flow cytometry. This model and associated assays have great value in accelerating the discovery of compounds for use in Mtb/HIV-1 co-infected patients. PMID:24388652

  12. Potential insight for drug discovery from high fidelity receptor-mediated transduction mechanisms in insects

    PubMed Central

    Raffa, Robert B.; Raffa, Kenneth F.

    2011-01-01

    Introduction There is a pervasive and growing concern about the small number of new pharmaceutical agents. There are many proposed explanations for this trend that do not involve the drug-discovery process per se, but the discovery process itself has also come under scrutiny. If the current paradigms are indeed not working, where are novel ideas to come from? Perhaps it is time to look to novel sources. Areas covered The receptor-signaling and 2nd-messenger transduction processes present in insects are quite similar to those in mammals (involving G proteins, ion channels, etc.). However, a review of these systems reveals an unprecedented degree of high potency and receptor selectivity to an extent greater than that modeled in most current drug-discovery approaches. Expert opinion A better understanding of insect receptor pharmacology could stimulate novel theoretical and practical ideas in mammalian pharmacology (drug discovery) and, conversely, the application of pharmacology and medicinal chemistry principles could stimulate novel advances in entomology (safer and more targeted control of pest species). PMID:21984882

  13. Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

    PubMed Central

    Pandey, Udai Bhan

    2011-01-01

    The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

  14. Curious discoveries in antiviral drug development: the role of serendipity.

    PubMed

    De Clercq, Erik

    2015-07-01

    Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses. PMID:25726922

  15. Tribbles pseudokinases: novel targets for chemical biology and drug discovery?

    PubMed

    Foulkes, Daniel M; Byrne, Dominic P; Bailey, Fiona P; Eyers, Patrick A

    2015-10-01

    Tribbles (TRIB) proteins are pseudokinase mediators of eukaryotic signalling that have evolved important roles in lipoprotein metabolism, immune function and cellular differentiation and proliferation. In addition, an evolutionary-conserved modulation of PI3K/AKT signalling pathways highlights them as novel and rather unusual pharmaceutical targets. The three human TRIB family members are uniquely defined by an acidic pseudokinase domain containing a 'broken' α C-helix and a MEK (MAPK/ERK)-binding site at the end of the putative C-lobe and a distinct C-terminal peptide motif that interacts directly with a small subset of cellular E3 ubiquitin ligases. This latter interaction drives proteasomal-dependent degradation of networks of transcription factors, whose rate of turnover determines the biological attributes of individual TRIB family members. Defining the function of individual Tribs has been made possible through evaluation of individual TRIB knockout mice, siRNA/overexpression approaches and genetic screening in flies, where the single TRIB gene was originally described 15 years ago. The rapidly maturing TRIB field is primed to exploit chemical biology approaches to evaluate endogenous TRIB signalling events in intact cells. This will help define how TRIB-driven protein-protein interactions and the atypical TRIB ATP-binding site, fit into cellular signalling modules in experimental scenarios where TRIB-signalling complexes remain unperturbed. In this mini-review, we discuss how small molecules can reveal rate-limiting signalling outputs and functions of Tribs in cells and intact organisms, perhaps serving as guides for the development of new drugs. We predict that appropriate small molecule TRIB ligands will further accelerate the transition of TRIB pseudokinase analysis into the mainstream of cell signalling. PMID:26517930

  16. Targeting human papillomavirus genome replication for antiviral drug discovery

    PubMed Central

    Archambault, Jacques; Melendy, Thomas

    2015-01-01

    Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein–protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics. PMID:23615820

  17. Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery

    PubMed Central

    Blundell, Tom L; Sibanda, Bancinyane L; Montalvão, Rinaldo Wander; Brewerton, Suzanne; Chelliah, Vijayalakshmi; Worth, Catherine L; Harmer, Nicholas J; Davies, Owen; Burke, David

    2006-01-01

    Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding. PMID:16524830

  18. Specificity quantification of biomolecular recognition and its implication for drug discovery

    NASA Astrophysics Data System (ADS)

    Yan, Zhiqiang; Wang, Jin

    2012-03-01

    Highly efficient and specific biomolecular recognition requires both affinity and specificity. Previous quantitative descriptions of biomolecular recognition were mostly driven by improving the affinity prediction, but lack of quantification of specificity. We developed a novel method SPA (SPecificity and Affinity) based on our funneled energy landscape theory. The strategy is to simultaneously optimize the quantified specificity of the ``native'' protein-ligand complex discriminating against ``non-native'' binding modes and the affinity prediction. The benchmark testing of SPA shows the best performance against 16 other popular scoring functions in industry and academia on both prediction of binding affinity and ``native'' binding pose. For the target COX-2 of nonsteroidal anti-inflammatory drugs, SPA successfully discriminates the drugs from the diversity set, and the selective drugs from non-selective drugs. The remarkable performance demonstrates that SPA has significant potential applications in identifying lead compounds for drug discovery.

  19. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma.

    PubMed

    Zhang, Kang; Zhang, Liangfang; Weinreb, Robert N

    2012-07-01

    Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities. PMID:22699774

  20. Drug discovery applications for KNIME: an open source data mining platform.

    PubMed

    Mazanetz, Michael P; Marmon, Robert J; Reisser, Catherine B T; Morao, Inaki

    2012-01-01

    Technological advances in high-throughput screening methods, combinatorial chemistry and the design of virtual libraries have evolved in the pursuit of challenging drug targets. Over the last two decades a vast amount of data has been generated within these fields and as a consequence data mining methods have been developed to extract key pieces of information from these large data pools. Much of this data is now available in the public domain. This has been helpful in the arena of drug discovery for both academic groups and for small to medium sized enterprises which previously would not have had access to such data resources. Commercial data mining software is sometimes prohibitively expensive and the alternate open source data mining software is gaining momentum in both academia and in industrial applications as the costs of research and development continue to rise. KNIME, the Konstanz Information Miner, has emerged as a leader in open source data mining tools. KNIME provides an integrated solution for the data mining requirements across the drug discovery pipeline through a visual assembly of data workflows drawing from an extensive repository of tools. This review will examine KNIME as an open source data mining tool and its applications in drug discovery. PMID:23110532

  1. Aptamer-Based Detection of Disease Biomarkers in Mouse Models for Chagas Drug Discovery

    PubMed Central

    de Araujo, Fernanda Fortes; Nagarkatti, Rana; Gupta, Charu; Marino, Ana Paula; Debrabant, Alain

    2015-01-01

    Drug discovery initiatives, aimed at Chagas treatment, have been hampered by the lack of standardized drug screening protocols and the absence of simple pre-clinical assays to evaluate treatment efficacy in animal models. In this study, we used a simple Enzyme Linked Aptamer (ELA) assay to detect T. cruzi biomarker in blood and validate murine drug discovery models of Chagas disease. In two mice models, Apt-29 ELA assay demonstrated that biomarker levels were significantly higher in the infected group compared to the control group, and upon Benznidazole treatment, their levels reduced. However, biomarker levels in the infected treated group did not reduce to those seen in the non-infected treated group, with 100% of the mice above the assay cutoff, suggesting that parasitemia was reduced but cure was not achieved. The ELA assay was capable of detecting circulating biomarkers in mice infected with various strains of T. cruzi parasites. Our results showed that the ELA assay could detect residual parasitemia in treated mice by providing an overall picture of the infection in the host. They suggest that the ELA assay can be used in drug discovery applications to assess treatment efficacy in-vivo. PMID:25569299

  2. Aptamer-based detection of disease biomarkers in mouse models for chagas drug discovery.

    PubMed

    de Araujo, Fernanda Fortes; Nagarkatti, Rana; Gupta, Charu; Marino, Ana Paula; Debrabant, Alain

    2015-01-01

    Drug discovery initiatives, aimed at Chagas treatment, have been hampered by the lack of standardized drug screening protocols and the absence of simple pre-clinical assays to evaluate treatment efficacy in animal models. In this study, we used a simple Enzyme Linked Aptamer (ELA) assay to detect T. cruzi biomarker in blood and validate murine drug discovery models of Chagas disease. In two mice models, Apt-29 ELA assay demonstrated that biomarker levels were significantly higher in the infected group compared to the control group, and upon Benznidazole treatment, their levels reduced. However, biomarker levels in the infected treated group did not reduce to those seen in the non-infected treated group, with 100% of the mice above the assay cutoff, suggesting that parasitemia was reduced but cure was not achieved. The ELA assay was capable of detecting circulating biomarkers in mice infected with various strains of T. cruzi parasites. Our results showed that the ELA assay could detect residual parasitemia in treated mice by providing an overall picture of the infection in the host. They suggest that the ELA assay can be used in drug discovery applications to assess treatment efficacy in-vivo. PMID:25569299

  3. Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

    PubMed Central

    Wilson, Christina; Terry, Alvin V.

    2015-01-01

    Schizophrenia is a devastating mental illness that is associated with a lifetime of disability. For patients to successfully function in society, the amelioration of disease symptoms is imperative. The recently published results of two large antipsychotic clinical trials (e.g., CATIE, CUtLASS) clearly exemplified the limitations of currently available treatment options for schizophrenia, and further highlighted the critical need for novel drug discovery and development in this field. One of the biggest challenges in schizophrenia-related drug discovery is to find an appropriate animal model of the illness so that novel hypotheses can be tested at the basic science level. A number of pharmacological, genetic, and neurodevelopmental models have been introduced; however, none of these models has been rigorously evaluated for translational relevance or to satisfy requirements of “face,” “construct” and “predictive” validity. Given the apparent polygenic nature of schizophrenia and the limited translational significance of pharmacological models, neurodevelopmental models may offer the best chance of success. The purpose of this review is to provide a general overview of the various neurodevelopmental models of schizophrenia that have been introduced to date, and to summarize their behavioral and neurochemical phenotypes that may be useful from a drug discovery and development standpoint. While it may be that, in the final analysis, no single animal model will satisfy all the requirements necessary for drug discovery purposes, several of the models may be useful for modeling various phenomenological and pathophysiological components of schizophrenia that could be targeted independently with separate molecules or multi-target drugs. PMID:20643635

  4. New challenges and inspired answers for anticancer drug discovery and development.

    PubMed

    Utsugi, Teruhiro

    2013-10-01

    Many pharmaceutical companies worldwide specialize in oncology drug development and marketing. Among them, we have continued to take up the challenge of understanding the metabolism of pyrimidines as essential components of deoxyribonucleic acid for many years, and have provided unique products such as UFT(®) and TS-1 for cancer patients. Using our cumulative experience and knowledge, we are currently developing novel agents such as TAS-114, a dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and TAS-102, a unique pyrimidine derivative inducing deoxyribonucleic acid dysfunction in cancer cells. Regarding molecular-targeted drugs, we have made huge efforts to establish ideal drug discovery platforms for the last several years. For kinase inhibitors, we established three core platforms such as a kinase-directed chemical library, a kinase assay panel and a target selection informatics system. The core platforms were further combined with peripheral technologies to measure essential parameters such as physicochemical properties, pharmacokinetics, efficacy and toxicities. Unique drug candidates have been identified at an early stage by assessing all important parameters. Several promising programs are proceeding simultaneously in the clinical or preclinical development stage such as TAS-115, a dual inhibitor of c-Met and vascular endothelial growth factor receptor, TAS-2104, a selective Aurora A inhibitor, TAS-117, an allosteric Akt inhibitor, TAS-2985, an irreversible fibroblast growth factor receptor inhibitor and TAS-2913, a T790M mutant selective epidermal growth factor receptor inhibitor. Other than kinase inhibitors, another drug discovery engine was established based on the fragment-based drug discovery technology. TAS-116, a new class of Hsp-90α/β inhibitor, is one of the products. Taiho's final goal is to provide innovative anticancer drugs together with companion diagnostics that are truly beneficial for patients. PMID

  5. New Challenges and Inspired Answers for Anticancer Drug Discovery and Development

    PubMed Central

    Utsugi, Teruhiro

    2013-01-01

    Many pharmaceutical companies worldwide specialize in oncology drug development and marketing. Among them, we have continued to take up the challenge of understanding the metabolism of pyrimidines as essential components of deoxyribonucleic acid for many years, and have provided unique products such as UFT® and TS-1 for cancer patients. Using our cumulative experience and knowledge, we are currently developing novel agents such as TAS-114, a dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and TAS-102, a unique pyrimidine derivative inducing deoxyribonucleic acid dysfunction in cancer cells. Regarding molecular-targeted drugs, we have made huge efforts to establish ideal drug discovery platforms for the last several years. For kinase inhibitors, we established three core platforms such as a kinase-directed chemical library, a kinase assay panel and a target selection informatics system. The core platforms were further combined with peripheral technologies to measure essential parameters such as physicochemical properties, pharmacokinetics, efficacy and toxicities. Unique drug candidates have been identified at an early stage by assessing all important parameters. Several promising programs are proceeding simultaneously in the clinical or preclinical development stage such as TAS-115, a dual inhibitor of c-Met and vascular endothelial growth factor receptor, TAS-2104, a selective Aurora A inhibitor, TAS-117, an allosteric Akt inhibitor, TAS-2985, an irreversible fibroblast growth factor receptor inhibitor and TAS-2913, a T790M mutant selective epidermal growth factor receptor inhibitor. Other than kinase inhibitors, another drug discovery engine was established based on the fragment-based drug discovery technology. TAS-116, a new class of Hsp-90α/β inhibitor, is one of the products. Taiho's final goal is to provide innovative anticancer drugs together with companion diagnostics that are truly beneficial for patients. PMID

  6. The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

    PubMed Central

    Salon, John A.; Lodowski, David T.

    2011-01-01

    Crucial as molecular sensors for many vital physiological processes, seven-transmembrane domain G protein-coupled receptors (GPCRs) comprise the largest family of proteins targeted by drug discovery. Together with structures of the prototypical GPCR rhodopsin, solved structures of other liganded GPCRs promise to provide insights into the structural basis of the superfamily's biochemical functions and assist in the development of new therapeutic modalities and drugs. One of the greatest technical and theoretical challenges to elucidating and exploiting structure-function relationships in these systems is the emerging concept of GPCR conformational flexibility and its cause-effect relationship for receptor-receptor and receptor-effector interactions. Such conformational changes can be subtle and triggered by relatively small binding energy effects, leading to full or partial efficacy in the activation or inactivation of the receptor system at large. Pharmacological dogma generally dictates that these changes manifest themselves through kinetic modulation of the receptor's G protein partners. Atomic resolution information derived from increasingly available receptor structures provides an entrée to the understanding of these events and practically applying it to drug design. Supported by structure-activity relationship information arising from empirical screening, a unified structural model of GPCR activation/inactivation promises to both accelerate drug discovery in this field and improve our fundamental understanding of structure-based drug design in general. This review discusses fundamental problems that persist in drug design and GPCR structural determination. PMID:21969326

  7. [Chapter 2. Transitions in drug-discovery technology and drug-development in Japan (1980-2010)].

    PubMed

    Sakakibara, Noriko; Yoshioka, Ryuzo; Matsumoto, Kazuo

    2014-01-01

    In 1970s, the material patent system was introduced in Japan. Since then, many Japanese pharmaceutical companies have endeavored to create original in-house products. From 1980s, many of the innovative products were small molecular drugs and were developed using powerful medicinal-chemical technologies. Among them were antibiotics and effective remedies for the digestive organs and circulatory organs. During this period, Japanese companies were able to launch some blockbuster drugs. At the same time, the pharmaceutical market, which had grown rapidly for two decades, was beginning to level off. From the late 1990s, drug development was slowing down due to the lack of expertise in biotechnology such as genetic engineering. In response to the circumstances, the research and development on biotechnology-based drugs such as antibody drugs have become more dynamic and popular at companies than small molecule drugs. In this paper, the writers reviewed in detail the transitions in drug discovery and development between 1980 and 2010. PMID:25272636

  8. Drugs That Target Dynamic Microtubules: A New Molecular Perspective

    PubMed Central

    Stanton, Richard A.; Gernert, Kim M.; Nettles, James H.; Aneja, Ritu

    2011-01-01

    Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work. PMID:21381049

  9. Discovery and explanation of drug-drug interactions via text mining.

    PubMed

    Percha, Bethany; Garten, Yael; Altman, Russ B

    2012-01-01

    Drug-drug interactions (DDIs) can occur when two drugs interact with the same gene product. Most available information about gene-drug relationships is contained within the scientific literature, but is dispersed over a large number of publications, with thousands of new publications added each month. In this setting, automated text mining is an attractive solution for identifying gene-drug relationships and aggregating them to predict novel DDIs. In previous work, we have shown that gene-drug interactions can be extracted from Medline abstracts with high fidelity - we extract not only the genes and drugs, but also the type of relationship expressed in individual sentences (e.g. metabolize, inhibit, activate and many others). We normalize these relationships and map them to a standardized ontology. In this work, we hypothesize that we can combine these normalized gene-drug relationships, drawn from a very broad and diverse literature, to infer DDIs. Using a training set of established DDIs, we have trained a random forest classifier to score potential DDIs based on the features of the normalized assertions extracted from the literature that relate two drugs to a gene product. The classifier recognizes the combinations of relationships, drugs and genes that are most associated with the gold standard DDIs, correctly identifying 79.8% of assertions relating interacting drug pairs and 78.9% of assertions relating noninteracting drug pairs. Most significantly, because our text processing method captures the semantics of individual gene-drug relationships, we can construct mechanistic pharmacological explanations for the newly-proposed DDIs. We show how our classifier can be used to explain known DDIs and to uncover new DDIs that have not yet been reported. PMID:22174296

  10. The Role of HTS in Drug Discovery at the University of Michigan

    PubMed Central

    Larsen, Martha J.; Larsen, Scott D.; Fribley, Andrew; Grembecka, Jolanta; Homan, Kristoff; Mapp, Anna; Haak, Andrew; Nikolovska-Coleska, Zaneta; Stuckey, Jeanne A.; Sun, Duxin

    2014-01-01

    High throughput screening (HTS) is an integral part of a highly collaborative approach to drug discovery at the University of Michigan. The HTS lab is one of four core centers that provide services to identify, produce, screen and follow-up on biomedical targets for faculty. Key features of this system are: protein cloning and purification, protein crystallography, small molecule and siRNA HTS, medicinal chemistry and pharmacokinetics. Therapeutic areas that have been targeted include anti-bacterial, metabolic, neurodegenerative, cardiovascular, anti-cancer and anti-viral. The centers work in a coordinated, interactive environment to affordably provide academic investigators with the technology, informatics and expertise necessary for successful drug discovery. This review provides an overview of these centers at the University of Michigan, along with case examples of successful collaborations with faculty. PMID:24409957

  11. Software Infrastructure for Computer-aided Drug Discovery and Development, a Practical Example with Guidelines.

    PubMed

    Moretti, Loris; Sartori, Luca

    2016-09-01

    In the field of Computer-Aided Drug Discovery and Development (CADDD) the proper software infrastructure is essential for everyday investigations. The creation of such an environment should be carefully planned and implemented with certain features in order to be productive and efficient. Here we describe a solution to integrate standard computational services into a functional unit that empowers modelling applications for drug discovery. This system allows users with various level of expertise to run in silico experiments automatically and without the burden of file formatting for different software, managing the actual computation, keeping track of the activities and graphical rendering of the structural outcomes. To showcase the potential of this approach, performances of five different docking programs on an Hiv-1 protease test set are presented. PMID:27546042

  12. Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review

    PubMed Central

    Csermely, Peter; Korcsmáros, Tamás; Kiss, Huba J.M.; London, Gábor; Nussinov, Ruth

    2013-01-01

    Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only gives a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The “central hit strategy” selectively targets central node/edges of the flexible networks of infectious agents or cancer cells to kill them. The “network influence strategy” works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach. PMID:23384594

  13. Novel data-mining methodologies for adverse drug event discovery and analysis.

    PubMed

    Harpaz, R; DuMouchel, W; Shah, N H; Madigan, D; Ryan, P; Friedman, C

    2012-06-01

    An important goal of the health system is to identify new adverse drug events (ADEs) in the postapproval period. Datamining methods that can transform data into meaningful knowledge to inform patient safety have proven essential for this purpose. New opportunities have emerged to harness data sources that have not been used within the traditional framework. This article provides an overview of recent methodological innovations and data sources used to support ADE discovery and analysis. PMID:22549283

  14. Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery.

    PubMed

    Chen, Fuyi; Becker, Albert; LoTurco, Joseph

    2016-01-01

    Many animal models have been developed to investigate the sources of central nervous system (CNS) tumor heterogeneity. Reviewed in this unit is a recently developed CNS tumor model using the piggyBac transposon system delivered by in utero electroporation, in which sources of tumor heterogeneity can be conveniently studied. Their applications for studying CNS tumors and drug discovery are also reviewed. © 2016 by John Wiley & Sons, Inc. PMID:26995546

  15. The role of big data and advanced analytics in drug discovery, development, and commercialization.

    PubMed

    Szlezák, N; Evers, M; Wang, J; Pérez, L

    2014-05-01

    In recent years, few ideas have captured the imagination of health-care practitioners as much as the advent of "big data" and the advanced analytical methods and technologies used to interpret it-it is a trend seen as having the potential to revolutionize biology, medicine, and health care.(1,2,3) As new types of data and tools become available, a unique opportunity is emerging for smarter and more effective discovery, development, and commercialization of innovative biopharmaceutical drugs. PMID:24642713

  16. Exploring chemical space for drug discovery using the chemical universe database.

    PubMed

    Reymond, Jean-Louis; Awale, Mahendra

    2012-09-19

    Herein we review our recent efforts in searching for bioactive ligands by enumeration and virtual screening of the unknown chemical space of small molecules. Enumeration from first principles shows that almost all small molecules (>99.9%) have never been synthesized and are still available to be prepared and tested. We discuss open access sources of molecules, the classification and representation of chemical space using molecular quantum numbers (MQN), its exhaustive enumeration in form of the chemical universe generated databases (GDB), and examples of using these databases for prospective drug discovery. MQN-searchable GDB, PubChem, and DrugBank are freely accessible at www.gdb.unibe.ch. PMID:23019491

  17. Exploring Chemical Space for Drug Discovery Using the Chemical Universe Database

    PubMed Central

    2012-01-01

    Herein we review our recent efforts in searching for bioactive ligands by enumeration and virtual screening of the unknown chemical space of small molecules. Enumeration from first principles shows that almost all small molecules (>99.9%) have never been synthesized and are still available to be prepared and tested. We discuss open access sources of molecules, the classification and representation of chemical space using molecular quantum numbers (MQN), its exhaustive enumeration in form of the chemical universe generated databases (GDB), and examples of using these databases for prospective drug discovery. MQN-searchable GDB, PubChem, and DrugBank are freely accessible at www.gdb.unibe.ch. PMID:23019491

  18. Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria.

    PubMed

    Soni, Isha; De Groote, Mary Ann; Dasgupta, Arunava; Chopra, Sidharth

    2016-01-01

    Non-tuberculous mycobacteria (NTM) infections are increasingly being reported worldwide. They are a major concern for healthcare professionals for multiple reasons, ranging from the intrinsic resistance of NTM to most conventionally utilized antimicrobials to inharmonious diagnostic criteria utilized for evaluation of NTM-infected patients, leading to high morbidity. In this review, we highlight the paucity of drugs having potent anti-NTM activity amongst the new antimicrobials currently under various stages of development for anti-tubercular activity and issue a call for the establishment of a concerted dedicated drug discovery pipeline targeting NTM. PMID:26515915

  19. High-performance thin layer chromatography: A powerful analytical technique in pharmaceutical drug discovery

    PubMed Central

    Attimarad, Mahesh; Ahmed, K. K. Mueen; Aldhubaib, Bandar E.; Harsha, Sree

    2011-01-01

    Analysis of pharmaceutical and natural compounds and newer drugs is commonly used in all the stages of drug discovery and development process. High-performance thin layer chromatography is one of the sophisticated instrumental techniques based on the full capabilities of thin layer chromatography. The advantages of automation, scanning, full optimization, selective detection principle, minimum sample preparation, hyphenation, and so on enable it to be a powerful analytical tool for chromatographic information of complex mixtures of pharmaceuticals, natural products, clinical samples, food stuffs, and so on. PMID:23781433

  20. The value of plants used in traditional medicine for drug discovery.

    PubMed Central

    Fabricant, D S; Farnsworth, N R

    2001-01-01

    In this review we describe and discuss several approaches to selecting higher plants as candidates for drug development with the greatest possibility of success. We emphasize the role of information derived from various systems of traditional medicine (ethnomedicine) and its utility for drug discovery purposes. We have identified 122 compounds of defined structure, obtained from only 94 species of plants, that are used globally as drugs and demonstrate that 80% of these have had an ethnomedical use identical or related to the current use of the active elements of the plant. We identify and discuss advantages and disadvantages of using plants as starting points for drug development, specifically those used in traditional medicine. PMID:11250806

  1. Shifting from the single- to the multitarget paradigm in drug discovery

    PubMed Central

    Medina-Franco, José L.; Giulianotti, Marc A.; Welmaker, Gregory S.; Houghten, Richard A.

    2013-01-01

    Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and highthroughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target–one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only ‘key’ compounds that fit with a single-target ‘lock’, but also ‘master key’ compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects). PMID:23340113

  2. Open Innovation Drug Discovery (OIDD): a potential path to novel therapeutic chemical space.

    PubMed

    Alvim-Gaston, Maria; Grese, Timothy; Mahoui, Abdelaziz; Palkowitz, Alan D; Pineiro-Nunez, Marta; Watson, Ian

    2014-01-01

    The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals. PMID:24283973

  3. Concise Review: Drug Discovery in the Age of the Induced Pluripotent Stem Cell

    PubMed Central

    Ko, Huaising C.

    2014-01-01

    For decades, the paradigm of drug discovery and development has relied on immortalized cell lines, animal models of human disease, and clinical trials. With the discovery of induced pluripotent stem cell (iPSC) technology in 2007, a new human in vitro drug testing platform has potentially augmented this set of tools by providing additional ways to screen compounds for safety and efficacy. The growing number of human disease models made with patient-specific iPSCs has made it possible to conduct research on a wide range of disorders, including rare diseases and those with multifactorial origin, as well as to simulate drug effects on difficult-to-obtain tissues such as brain and cardiac muscle. Toxicity and teratogenicity assays developed with iPSC-derived cells can also provide an additional layer of safety before advancing drugs to clinical trials. The incorporation of iPSC technology into drug therapy development holds promise as a more powerful and nuanced approach to personalized medicine. PMID:24493856

  4. Challenges for drug discovery - a case study of urokinase receptor inhibition

    PubMed Central

    Chen, Zhuo; Lin, Lin; Huai, Qing; Huang, Mingdong

    2009-01-01

    Urokinase receptor (uPAR) is a widely recognized target for potential treatment of cancer. The development of uPAR inhibitors has been going on for over a decade. Despite the identification and validation of many highly potent hits using screening or medicinal approaches, none of them has been moved further along the drug discovery pipeline. The development of uPAR inhibitors exemplifies several challenges now faced by drug discovery. These include 1) hydrophobicity and thus poor bioavailability of the inhibitors from screening approaches; 2) specificity of the inhibitor, where a peptidyl inhibitor causes conformational change of the receptor; 3) species specificity, where some inhibitors developed based on the human receptor do not inhibit the murine receptor and thus cannot be validated in mouse models. The recently determined crystal structures of uPAR in complex with its ligand or inhibitor not only provide the structural insight to understand these challenges but also offer a potential solution for further inhibitor development and thus illustrate the importance of structural information in facilitating drug discovery. PMID:20025562

  5. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery.

    PubMed

    Ghose, Arup K; Herbertz, Torsten; Hudkins, Robert L; Dorsey, Bruce D; Mallamo, John P

    2012-01-18

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer's disease (AD), Parkinson's disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood-brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å(2) (25-60 Å(2)), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740-970 Å(3), (vi) solvent accessible surface area of 460-580 Å(2), and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  6. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

    PubMed Central

    2011-01-01

    The central nervous system (CNS) is the major area that is affected by aging. Alzheimer’s disease (AD), Parkinson’s disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood–brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å2 (25–60 Å2), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740–970 Å3, (vi) solvent accessible surface area of 460–580 Å2, and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The

  7. Hurdles in anticancer drug development from a regulatory perspective.

    PubMed

    Jonsson, Bertil; Bergh, Jonas

    2012-04-01

    Between January 2001 and January 2012, 48 new medicinal products for cancer treatment were licensed within the EU, and 77 new indications were granted for products already licensed. In some cases, a major improvement to existing therapies was achieved, for example, trastuzumab in breast cancer. In other cases, new fields for effective drug therapy opened up, such as in chronic myeloid leukemia, and renal-cell carcinoma. In most cases, however, the benefit-risk balance was considered to be only borderline favorable. Based on our assessment of advice procedures for marketing authorization, 'need for speed' seems to be the guiding principle in anticancer drug development. Although, for drugs that make a difference, early licensure is of obvious importance to patients, this is less evident in the case of borderline drugs. Without proper incentives and with hurdles inside and outside companies, a change in drug development cannot be expected; drugs improving benefit-risk modestly over available therapies will be brought forward towards licensure. In this Perspectives article, we discuss some hurdles to biomarker-driven drug development and provide some suggestions to overcome them. PMID:22349015

  8. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

    PubMed Central

    Van Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Alemán Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jürgen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Belen Cassera, Maria; Chih-Chien Cheng, Ken; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colón-López, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D’Alessandro, Sarah; Le Dang, Na; Delves, Michael; Du, Alan Y.; Duffy, Sandra; Abd El-Salam El-Sayed, Shimaa; Ferdig, Michael T.; Fernández Robledo, José A.; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Gamo, Francisco Javier; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Naranuntarat Jensen, Amornrat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinás, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Medina Vera, Iset; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Morais Rodrigues da Costa, Francielly; Müller, Joachim; Muriana, Arantza; Nakazawa Hewitt, Stephen; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Abdo Rizk, Mohamed; Ruecker, Andrea; St. Onge, Robert; Salgado Ferreira, Rafaela; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Silva Villela, Filipe; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmüller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Voong Vinh, Phat; Vu, Hoan; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoît; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.

    2016-01-01

    A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal

  9. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

    PubMed

    Van Voorhis, Wesley C; Adams, John H; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H; Alano, Pietro; Alday, Aintzane; Alemán Resto, Yesmalie; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T; Avery, Simon V; Avery, Vicky M; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Jürgen; Boucher, Lauren E; Boyom, Fabrice F; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Belen Cassera, Maria; Chih-Chien Cheng, Ken; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L; Colón-López, Daisy D; Corbett, Yolanda; Crowther, Gregory J; Cowan, Noemi; D'Alessandro, Sarah; Le Dang, Na; Delves, Michael; DeRisi, Joseph L; Du, Alan Y; Duffy, Sandra; Abd El-Salam El-Sayed, Shimaa; Ferdig, Michael T; Fernández Robledo, José A; Fidock, David A; Florent, Isabelle; Fokou, Patrick V T; Galstian, Ani; Gamo, Francisco Javier; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M; Guha, Rajarshi; Guiguemde, W Armand; Gural, Nil; Guy, R Kiplin; Hansen, Michael A E; Hanson, Kirsten K; Hemphill, Andrew; Hooft van Huijsduijnen, Rob; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A; Jadhav, Ajit; Naranuntarat Jensen, Amornrat; Jensen, Laran T; Jiang, Rays H Y; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P; Kyle, Dennis E; Lafuente, Maria Jose; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M; Li, Fengwu; Little, David; Liu, Liqiong; Llinás, Manuel; Loza, Maria I; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R; March, Sandra; McGowan, Sheena; Medina Vera, Iset; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N; Misra, Raj N; Moon, Seunghyun; Moore, John P; Morais Rodrigues da Costa, Francielly; Müller, Joachim; Muriana, Arantza; Nakazawa Hewitt, Stephen; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Pham, Ngoc; Prats, Sarah; Plouffe, David M; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J; Rice, Christopher A; Abdo Rizk, Mohamed; Ruecker, Andrea; St Onge, Robert; Salgado Ferreira, Rafaela; Samra, Jasmeet; Robinett, Natalie G; Schlecht, Ulrich; Schmitt, Marjorie; Silva Villela, Filipe; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A; Soldati, Thierry; Spitzmüller, Andreas; Stamm, Serge Maximilian; Sullivan, David J; Sullivan, William; Suresh, Sundari; Suzuki, Brian M; Suzuki, Yo; Swamidass, S Joshua; Taramelli, Donatella; Tchokouaha, Lauve R Y; Theron, Anjo; Thomas, David; Tonissen, Kathryn F; Townson, Simon; Tripathi, Abhai K; Trofimov, Valentin; Udenze, Kenneth O; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M; Voong Vinh, Phat; Vu, Hoan; Watanabe, Nao-Aki; Weatherby, Kate; White, Pamela M; Wilks, Andrew F; Winzeler, Elizabeth A; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H A; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoît; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A

    2016-07-01

    A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal

  10. Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.

    PubMed

    McBride, Christopher; Cheruvallath, Zacharia; Komandla, Mallareddy; Tang, Mingnam; Farrell, Pamela; Lawson, J David; Vanderpool, Darin; Wu, Yiqin; Dougan, Douglas R; Plonowski, Artur; Holub, Corine; Larson, Chris

    2016-06-15

    Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally. PMID:27136719

  11. A clinical perspective on mucoadhesive buccal drug delivery systems

    PubMed Central

    Gilhotra, Ritu M; Ikram, Mohd; Srivastava, Sunny; Gilhotra, Neeraj

    2014-01-01

    Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems. PMID:24683406

  12. The application of the open pharmacological concepts triple store (open PHACTS) to support drug discovery research.

    PubMed

    Ratnam, Joseline; Zdrazil, Barbara; Digles, Daniela; Cuadrado-Rodriguez, Emiliano; Neefs, Jean-Marc; Tipney, Hannah; Siebes, Ronald; Waagmeester, Andra; Bradley, Glyn; Chau, Chau Han; Richter, Lars; Brea, Jose; Evelo, Chris T; Jacoby, Edgar; Senger, Stefan; Loza, Maria Isabel; Ecker, Gerhard F; Chichester, Christine

    2014-01-01

    Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery. PMID:25522365

  13. The Application of the Open Pharmacological Concepts Triple Store (Open PHACTS) to Support Drug Discovery Research

    PubMed Central

    Ratnam, Joseline; Zdrazil, Barbara; Digles, Daniela; Cuadrado-Rodriguez, Emiliano; Neefs, Jean-Marc; Tipney, Hannah; Siebes, Ronald; Waagmeester, Andra; Bradley, Glyn; Chau, Chau Han; Richter, Lars; Brea, Jose; Evelo, Chris T.; Jacoby, Edgar; Senger, Stefan; Loza, Maria Isabel; Ecker, Gerhard F.; Chichester, Christine

    2014-01-01

    Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery. PMID:25522365

  14. Cancer drug discovery by repurposing: teaching new tricks to old dogs.

    PubMed

    Gupta, Subash C; Sung, Bokyung; Prasad, Sahdeo; Webb, Lauren J; Aggarwal, Bharat B

    2013-09-01

    Progressively increasing failure rates, high cost, poor bioavailability, poor safety, limited efficacy, and a lengthy design and testing process associated with cancer drug development have necessitated alternative approaches to drug discovery. Exploring established non-cancer drugs for anticancer activity provides an opportunity rapidly to advance therapeutic strategies into clinical trials. The impetus for development of cancer therapeutics from non-cancer drugs stems from the fact that different diseases share common molecular pathways and targets in the cell. Common molecular origins of diverse diseases have been discovered through advancements in genomics, proteomics, and informatics technologies, as well as through the development of analytical tools that allow researchers simultaneously to screen large numbers of existing drugs against a particular disease target. Thus, drugs originally identified as antitussive, sedative, analgesic, antipyretic, antiarthritic, anesthetic, antidiabetic, muscle relaxant, immunosuppressant, antibiotic, antiepileptic, cardioprotective, antihypertensive, erectile function enhancing, or angina relieving are being repurposed for cancer. This review describes the repurposing of these drugs for cancer treatment. PMID:23928289

  15. Development and application of high-performance affinity beads: toward chemical biology and drug discovery.

    PubMed

    Sakamoto, Satoshi; Kabe, Yasuaki; Hatakeyama, Mamoru; Yamaguchi, Yuki; Handa, Hiroshi

    2009-01-01

    In drug development research, the elucidation and understanding of the interactions between physiologically active substances and proteins that numerous genes produce is important. Currently, most commercially available drugs and physiologically active substances have been brought to market without knowledge of factors interacting with the drugs and the substances. Affinity purification is a useful and powerful technique employed to understand factors that are targeted by drugs and physiologically active substances. However, use of conventional matrices for affinity chromatography often causes a decrease in efficiency of affinity purification and, as a result, more practical matrices for affinity purification have been developed for application in drug discovery research. In this paper, we describe the development of high-performance affinity beads (SG beads and FG beads) that enable one-step affinity purification of drug targets and the elucidation of the mechanism of the action of the drugs. We also describe a chemical screening system using our affinity beads. We hope that utilization of the affinity beads will contribute to the progress of research in chemical biology. PMID:19243077

  16. Recent advances using zebrafish animal models for muscle disease drug discovery

    PubMed Central

    Maves, Lisa

    2015-01-01

    Introduction Animal models have enabled great progress in the discovery and understanding of pharmacological approaches for treating muscle diseases like Duchenne muscular dystrophy. Areas covered With this article, the author provides the reader with a description of the zebrafish animal model, which has been employed to identify and study pharmacological approaches to muscle disease. In particular, the author focuses on how both large-scale chemical screens and targeted drug treatment studies have established zebrafish as an important model for muscle disease drug discovery. Expert opinion There are a number of opportunities arising for the use of zebrafish models for further developing pharmacological approaches to muscle diseases, including studying drug combination therapies and utilizing genome editing to engineer zebrafish muscle disease models. It is the author’s particular belief that the availability of a wide range of zebrafish transgenic strains for labeling immune cell types, combined with live imaging and drug treatment of muscle disease models, should allow for new elegant studies demonstrating how pharmacological approaches might influence inflammation and the immune response in muscle disease. PMID:24931439

  17. Systems pharmacology: bridging systems biology and pharmacokinetics-pharmacodynamics (PKPD) in drug discovery and development.

    PubMed

    van der Graaf, Piet H; Benson, Neil

    2011-07-01

    Mechanistic PKPD models are now advocated not only by academic and industrial researchers, but also by regulators. A recent development in this area is based on the growing realisation that innovation could be dramatically catalysed by creating synergy at the interface between Systems Biology and PKPD, two disciplines which until now have largely existed in 'parallel universes' with a limited track record of impactful collaboration. This has led to the emergence of systems pharmacology. Broadly speaking, this is the quantitative analysis of the dynamic interactions between drug(s) and a biological system to understand the behaviour of the system as a whole, as opposed to the behaviour of its individual constituents; thus, it has become the interface between PKPD and systems biology. It applies the concepts of Systems Engineering, Systems Biology, and PKPD to the study of complex biological systems through iteration between computational and/or mathematical modelling and experimentation. Application of systems pharmacology can now impact across all stages of drug research and development, ranging from very early discovery programs to large-scale Phase 3/4 patient studies, and has the potential to become an integral component of a new 'enhanced quantitative drug discovery and development' (EQD3) R&D paradigm. PMID:21560018

  18. Tango assay for ligand-induced GPCR-β-arrestin2 interaction: Application in drug discovery.

    PubMed

    Dogra, Shalini; Sona, Chandan; Kumar, Ajeet; Yadav, Prem N

    2016-01-01

    G protein-coupled receptors (GPCRs) are widely known to modulate almost all physiological functions and have been demonstrated over the time as therapeutic targets for wide gamut of diseases. The design and implementation of high-throughput GPCR-based assays that permit the efficient screening of large compound libraries to discover novel drug candidates are essential for a successful drug discovery endeavor. Usually, GPCR-based functional assays depend primarily on the measurement of G protein-mediated second messenger generation. However, with advent of advanced molecular biology tools and increased understanding of GPCR signal transduction, many G protein-independent pathways such as β-arrestin translocation are being utilized to detect the activity of GPCRs. These assays provide additional information on functional selectivity (also known as biased agonism) of compounds that could be harnessed to develop pathway-selective drug candidates to reduce the adverse effects associated with given GPCR target. In this chapter, we describe the basic principle, detailed methodologies and assay setup, result analysis and data interpretations of the β-arrestin2 Tango assay, and its comparison with cell-based G protein-dependent GPCR assays, which could be employed in a simple academic setup to facilitate GPCR-based drug discovery. PMID:26928547

  19. How might we increase success in marine-based drug discovery?

    PubMed

    Desbois, Andrew P

    2014-09-01

    Drug discovery from marine organisms has been underway for > 60 years and there have been notable successes in discovering, developing and introducing clinical agents derived from marine sources. Such examples include: the analgesic ziconotide and the anti cancer compound trabectedin. However, in light of the pressing need for new drugs, particularly those with anti-infective and anticancer properties, there is strong justification for increased exploration of marine organisms as sources of novel compounds. This article considers approaches that might enhance our chances of delivering new medicines from marine-based drug discovery efforts. Consideration is given to the organisms and habitats deserving of more attention and how we might make best use of these marine genetic resources. In particular, the opportunities offered by synthetic biology are highlighted because these methods allow drug discoverers to explore pathways in 'non-culturable' species and turn on natural product biosynthesis genes that are difficult to activate under laboratory conditions (so-called 'silent' gene clusters). PMID:24909595

  20. A Multimodal Data Analysis Approach for Targeted Drug Discovery Involving Topological Data Analysis (TDA).

    PubMed

    Alagappan, Muthuraman; Jiang, Dadi; Denko, Nicholas; Koong, Albert C

    2016-01-01

    In silico drug discovery refers to a combination of computational techniques that augment our ability to discover drug compounds from compound libraries. Many such techniques exist, including virtual high-throughput screening (vHTS), high-throughput screening (HTS), and mechanisms for data storage and querying. However, presently these tools are often used independent of one another. In this chapter, we describe a new multimodal in silico technique for the hit identification and lead generation phases of traditional drug discovery. Our technique leverages the benefits of three independent methods-virtual high-throughput screening, high-throughput screening, and structural fingerprint analysis-by using a fourth technique called topological data analysis (TDA). We describe how a compound library can be independently tested with vHTS, HTS, and fingerprint analysis, and how the results can be transformed into a topological data analysis network to identify compounds from a diverse group of structural families. This process of using TDA or similar clustering methods to identify drug leads is advantageous because it provides a mechanism for choosing structurally diverse compounds while maintaining the unique advantages of already established techniques such as vHTS and HTS. PMID:27325272

  1. Contemporary review of drug-induced pancreatitis: A different perspective.

    PubMed

    Hung, Whitney Y; Abreu Lanfranco, Odaliz

    2014-11-15

    Although gallstone and alcohol use have been considered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are associated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pancreatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal relationship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classification systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continuously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifactorial nature of acute pancreatitis call for a different approach. In this article, we review the potential mechanisms of drug induced acute pancreatitis and provide the perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pancreatitis with limited data. PMID:25400984

  2. Contemporary review of drug-induced pancreatitis: A different perspective

    PubMed Central

    Hung, Whitney Y; Abreu Lanfranco, Odaliz

    2014-01-01

    Although gallstone and alcohol use have been considered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are associated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pancreatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal relationship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classification systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continuously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifactorial nature of acute pancreatitis call for a different approach. In this article, we review the potential mechanisms of drug induced acute pancreatitis and provide the perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pancreatitis with limited data. PMID:25400984

  3. Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

    PubMed Central

    Kourtesi, Christina; Ball, Anthony R; Huang, Ying-Ying; Jachak, Sanjay M; Vera, D Mariano A; Khondkar, Proma; Gibbons, Simon; Hamblin, Michael R; Tegos, George P

    2013-01-01

    Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches. PMID:23569468

  4. Protein Traffic Disorders: an Effective High-Throughput Fluorescence Microscopy Pipeline for Drug Discovery

    PubMed Central

    Botelho, Hugo M.; Uliyakina, Inna; Awatade, Nikhil T.; Proença, Maria C.; Tischer, Christian; Sirianant, Lalida; Kunzelmann, Karl; Pepperkok, Rainer; Amaral, Margarida D.

    2015-01-01

    Plasma membrane proteins are essential molecules in the cell which mediate interactions with the exterior milieu, thus representing key drug targets for present pharma. Not surprisingly, protein traffic disorders include a large range of diseases sharing the common mechanism of failure in the respective protein to reach the plasma membrane. However, specific therapies for these diseases are remarkably lacking. Herein, we report a robust platform for drug discovery applied to a paradigmatic genetic disorder affecting intracellular trafficking – Cystic Fibrosis. This platform includes (i) two original respiratory epithelial cellular models incorporating an inducible double-tagged traffic reporter; (ii) a plasma membrane protein traffic assay for high-throughput microscopy screening; and (iii) open-source image analysis software to quantify plasma membrane protein traffic. By allowing direct scoring of compounds rescuing the basic traffic defect, this platform enables an effective drug development pipeline, which can be promptly adapted to any traffic disorder-associated protein and leverage therapy development efforts. PMID:25762484

  5. Inhibition of Microglia Activation as a Phenotypic Assay in Early Drug Discovery

    PubMed Central

    Figuera-Losada, Mariana; Rojas, Camilo; Slusher, Barbara S.

    2014-01-01

    Complex biological processes such as inflammation, cell death, migration, proliferation, and the release of biologically active molecules can be used as outcomes in phenotypic assays during early stages of drug discovery. Although target-based approaches have been widely used over the past decades, a disproportionate number of first-in-class drugs have been identified using phenotypic screening. This review details phenotypic assays based on inhibition of microglial activation and their utility in primary and secondary screening, target validation, and pathway elucidation. The role of microglia, both in normal as well as in pathological conditions such as chronic neurodegenerative diseases, is reviewed. Methodologies to assess microglia activation in vitro are discussed in detail, and classes of therapeutic drugs known to decrease the proinflammatory and cytotoxic responses of activated microglia are appraised, including inhibitors of glutaminase, cystine/glutamate antiporter, nuclear factor κB, and mitogen-activated protein kinases. PMID:23945875

  6. Drug-Discovery Pipeline for Novel Inhibitors of the Androgen Receptor.

    PubMed

    Dalal, Kush; Munuganti, Ravi; Morin, Hélène; Lallous, Nada; Rennie, Paul S; Cherkasov, Artem

    2016-01-01

    The androgen receptor (AR) is an important regulator of genes responsible for the development and recurrence of prostate cancer. Current therapies for this disease rely on small-molecule inhibitors that block the transcriptional activity of the AR. Recently, major advances in the development of novel AR inhibitors resulted from X-ray crystallographic information on the receptor and utilization of in silico drug design synergized with rigorous experimental testing.Herein, we describe a drug-discovery pipeline for in silico screening for small molecules that target an allosteric region on the AR termed the binding-function 3 (BF3) site. Following the identification of potential candidates, the compounds are tested in cell culture and biochemical assays for their ability to interact with and inhibit the AR. The described pipeline is readily accessible and could be applied in drug design efforts toward any surface-exposed region on the AR or other related steroid nuclear receptor. PMID:27246333

  7. Advances in Protein NMR Impacting Drug Discovery Provided by the NIGMS Protein Structure Initiative

    PubMed Central

    Montelione, Gaetano T.; Szyperski, Thomas

    2014-01-01

    Rational drug design relies on three-dimensional structures of biological macromolecules, especially proteins. Structural genomics high-throughput (HTP) structure determination platforms established by the NIH Protein Structure Initiative are uniquely suited to provide these structures. NMR plays a critical role since (i) many important protein targets do not form single crystals required for X-ray diffraction and (ii) NMR can provide valuable structural and dynamic information on proteins and their drug complexes that cannot be obtained with X-ray crystallography. In this article, recent advances of NMR driven by structural genomics projects are reviewed. These advances promise that future pharmaceutical discovery and design of drugs can increasingly rely on protocols for rapid and accurate NMR structure determination. PMID:20443167

  8. Improving understanding of chromatin regulatory proteins and potential implications for drug discovery.

    PubMed

    Rafehi, Haloom; Khan, Abdul Waheed; El-Osta, Assam

    2016-04-01

    Many epigenetic-based therapeutics, including drugs such as histone deacetylase inhibitors, are now used in the clinic or are undergoing advanced clinical trials. The study of chromatin-modifying proteins has benefited from the rapid advances in high-throughput sequencing methods, the organized efforts of major consortiums and by individual groups to profile human epigenomes in diverse tissues and cell types. However, while such initiatives have carefully characterized healthy human tissue, disease epigenomes and drug-epigenome interactions remain very poorly understood. Reviewed here is how high-throughput sequencing improves our understanding of chromatin regulator proteins and the potential implications for the study of human disease and drug development and discovery. PMID:26923902

  9. Protein traffic disorders: an effective high-throughput fluorescence microscopy pipeline for drug discovery.

    PubMed

    Botelho, Hugo M; Uliyakina, Inna; Awatade, Nikhil T; Proença, Maria C; Tischer, Christian; Sirianant, Lalida; Kunzelmann, Karl; Pepperkok, Rainer; Amaral, Margarida D

    2015-01-01

    Plasma membrane proteins are essential molecules in the cell which mediate interactions with the exterior milieu, thus representing key drug targets for present pharma. Not surprisingly, protein traffic disorders include a large range of diseases sharing the common mechanism of failure in the respective protein to reach the plasma membrane. However, specific therapies for these diseases are remarkably lacking. Herein, we report a robust platform for drug discovery applied to a paradigmatic genetic disorder affecting intracellular trafficking - Cystic Fibrosis. This platform includes (i) two original respiratory epithelial cellular models incorporating an inducible double-tagged traffic reporter; (ii) a plasma membrane protein traffic assay for high-throughput microscopy screening; and (iii) open-source image analysis software to quantify plasma membrane protein traffic. By allowing direct scoring of compounds rescuing the basic traffic defect, this platform enables an effective drug development pipeline, which can be promptly adapted to any traffic disorder-associated protein and leverage therapy development efforts. PMID:25762484

  10. Click chemistry patents and their impact on drug discovery and chemical biology.

    PubMed

    Xu, Hua; Jones, Lyn H

    2015-01-01

    First introduced by K Barry Sharpless in 2001, the term 'click chemistry' soon became a widely used description of chemical reactions that proceed rapidly, cleanly and in a manner that is often compatible with aqueous solutions. Click chemistry is frequently employed throughout the process of drug discovery, and greatly helps advance research programs in the pharmaceutical industry. It facilitates library synthesis to support medicinal chemistry optimization, helps identify the targets and off-targets of drug candidates, and can facilitate the determination of drug efficacy in clinical trials. In the last decade, a large number of patent applications covering the various types and utilities of click chemistry have been filed. In this review, we provide the first analysis of click chemistry applications. PMID:25853470

  11. Venoms, toxins and derivatives from the Brazilian fauna: valuable sources for drug discovery.

    PubMed

    De Marco Almeida, Flávia; de Castro Pimenta, Adriano Monteiro; Oliveira, Mônica Cristina; De Lima, Maria Elena

    2015-06-25

    Animal venoms have been widely investigated throughout the world. The great number of biotechnological articles as well as patent applications in the field of drug discovery based on these compounds indicates how important the source is. This review presents a list of the most studied Brazilian venomous animal species and shows the most recent patent applications filed from 2000 to 2013, which comprise Brazilian venoms, toxins and derivatives. We analyze the data according to the species, the type of products claimed and the nationality of the inventors. Fifty-five patent applications were found, involving 8 genera. Crotalus, Lachesis, Bothrops and Loxosceles represented 78% of the patent applications. The other 22% were represented by Phoneutria, Tityus, Acanthoscurria and Phyllomedusa. Most of the inventions (42%) involved anticancer, immunomodulator or antimicrobial drugs, while 13% involved anti-venoms and vaccines, 11% involved hypotensive compositions, 9% involved antinociceptive and/or anti-inflammatory compositions, and the other 25% involved methods, kits or compositions for various purposes. Brazilian inventors filed 49% of the patent applications, but other countries, mainly the United States of America, Germany, Russia and France, also filed patent applications claiming products comprising venoms, toxins and/or derivatives from the Brazilian fauna. Brazil holds an important number of patent applications which mostly belong to universities and research institutes, but the pharmaceutical industry in this field is still weak in Brazil. Although, Brazilian venomous animal species have been reported in drug discovery throughout the world, many species remain to be explored as valuable and promising tools for drug discovery and development. PMID:26109299

  12. Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling

    PubMed Central

    Flobak, Åsmund; Baudot, Anaïs; Remy, Elisabeth; Thommesen, Liv; Thieffry, Denis; Kuiper, Martin; Lægreid, Astrid

    2015-01-01

    Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible. Recent efforts to computationally predict drug combination responses retain this experimental search space, as model definitions typically rely on extensive drug perturbation data. We developed a dynamical model representing a cell fate decision network in the AGS gastric cancer cell line, relying on background knowledge extracted from literature and databases. We defined a set of logical equations recapitulating AGS data observed in cells in their baseline proliferative state. Using the modeling software GINsim, model reduction and simulation compression techniques were applied to cope with the vast state space of large logical models and enable simulations of pairwise applications of specific signaling inhibitory chemical substances. Our simulations predicted synergistic growth inhibitory action of five combinations from a total of 21 possible pairs. Four of the predicted synergies were confirmed in AGS cell growth real-time assays, including known effects of combined MEK-AKT or MEK-PI3K inhibitions, along with novel synergistic effects of combined TAK1-AKT or TAK1-PI3K inhibitions. Our strategy reduces the dependence on a priori drug perturbation experimentation for well-characterized signaling networks, by demonstrating that a model predictive of combinatorial drug effects can be inferred from background knowledge on unperturbed and proliferating cancer cells. Our modeling approach can thus contribute to preclinical discovery of efficient anticancer drug combinations, and thereby to development of strategies to tailor treatment to individual cancer patients. PMID:26317215

  13. Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs.

    PubMed

    Appendino, Giovanni; Minassi, Alberto; Taglialatela-Scafati, Orazio

    2014-07-01

    Covering: up to December 2013. Over the past decade, there has been a growing transition in recreational drugs from natural materials (marijuana, hashish, opium), natural products (morphine, cocaine), or their simple derivatives (heroin), to synthetic agents more potent than their natural prototypes, which are sometimes less harmful in the short term, or that combine properties from different classes of recreational prototypes. These agents have been named smart drugs, and have become popular both for personal consumption and for collective intoxication at rave parties. The reasons for this transition are varied, but are mainly regulatory and commercial. New analogues of known illegal intoxicants are invisible to most forensic detection techniques, while the alleged natural status and the lack of avert acute toxicity make them appealing to a wide range of users. On the other hand, the advent of the internet has made possible the quick dispersal of information among users and the on-line purchase of these agents and/or the precursors for their synthesis. Unlike their natural products chemotypes (ephedrine, mescaline, cathinone, psilocybin, THC), most new drugs of abuse are largely unfamiliar to the organic chemistry community as well as to health care providers. To raise awareness of the growing plague of smart drugs we have surveyed, in a medicinal chemistry fashion, their development from natural products leads, their current methods of production, and the role that clandestine home laboratories and underground chemists have played in the surge of popularity of these drugs. PMID:24823967

  14. Drug discovery alliances in India--indications, targets, and new chemical entities.

    PubMed

    Differding, Edmond

    2014-01-01

    Global pharmaceutical and biotechnology companies have been building increasingly on the skills and services offered by Indian biotech companies through strategic collaborative partnerships and alliances to fuel their in-house discovery and development pipelines. With the exception of generic press releases, however, very little has been published on the process and progress of drug discovery itself, such as the targets or modes of action involved, nor on the scientific output of such collaborations, and therefore on new chemical entities coming out of India through research collaborations. This Essay provides an analytical review of recent patents, patent applications, and peer-reviewed publications of major research alliances. It aims at highlighting their scientific output as well as the considerable bandwidth of targets and therapeutic areas involved. PMID:24136820

  15. Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.

    PubMed

    Kothiwale, Sandeepkumar; Borza, Corina M; Lowe, Edward W; Pozzi, Ambra; Meiler, Jens

    2015-02-01

    Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable. PMID:25284748

  16. Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery

    PubMed Central

    Kothiwale, Sandeepkumar; Borza, Corina M.; Lowe, Will; Pozzi, Ambra; Meiler, Jens

    2014-01-01

    Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable. PMID:25284748

  17. And if the discovery of new drugs for the treatment of brain diseases depends on Asian countries?

    PubMed Central

    Kraus, Jean-Louis

    2014-01-01

    At the present time, developed countries are making a huge financial effort to support neuroscience research programs, particularly in the fields of advanced research and treatment of brain diseases and mental disorders. A part of this financial support is devoted to drug discovery programs. The purpose of this communication is to focus on the different parameters (economic, social, and scientific) allowing for the prominent belief that the discovery of new efficient drugs to treat brain disease to an increasing extent is likely to emanate from the Asian countries. A special focus on drug research and discovery in France reveals that, due to the current social context, the lack of small pharmaceutical ventures, the Mediator drug scandal, and the economic situation, the potential for discovering and developing new drugs is dramatically declining. PMID:27226835

  18. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods.

    PubMed

    Graziose, Rocky; Lila, Mary Ann; Raskin, Ilya

    2010-03-01

    Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements. PMID:20156139

  19. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

    PubMed Central

    NITULESCU, GEORGE MIHAI; MARGINA, DENISA; JUZENAS, PETRAS; PENG, QIAN; OLARU, OCTAVIAN TUDOREL; SALOUSTROS, EMMANOUIL; FENGA, CONCETTINA; SPANDIDOS, DEMETRIOS A.; LIBRA, MASSIMO; TSATSAKIS, ARISTIDIS M.

    2016-01-01

    Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo-angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)-competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy. PMID:26698230

  20. Structural Biology Contributions to the Discovery of Drugs to Treat Chronic Myelogenous Leukemia

    NASA Astrophysics Data System (ADS)

    Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    This case study illustrates how the determination of multiple co-crystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery efforts leading to the design of nilotinib, a newly approved therapy for imatinib-intolerant and - resistant chronic myelogenous leukemia. Chronic myelogenous leukemia (CML) results from the BCR-Abl onco-protein, which possesses a constitutively activated Abl tyrosine kinase domain. Although many chronic-phase CML patients treated with imatinib as first-line therapy maintain excellent, durable responses, patients who have progressed to advanced-stage CML frequently fail, or lose their response to therapy, often due to the emergence of drug-resistant mutants of the protein. More than 60 such point mutations have been detected in imatinib-resistant patients. We determined the crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small molecule Abl inhibitors, with the aim of understanding the molecular basis for resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way this information is used to support drug discovery.

  1. Weighted similarity-based clustering of chemical structures and bioactivity data in early drug discovery.

    PubMed

    Perualila-Tan, Nolen Joy; Shkedy, Ziv; Talloen, Willem; Göhlmann, Hinrich W H; Moerbeke, Marijke Van; Kasim, Adetayo

    2016-08-01

    The modern process of discovering candidate molecules in early drug discovery phase includes a wide range of approaches to extract vital information from the intersection of biology and chemistry. A typical strategy in compound selection involves compound clustering based on chemical similarity to obtain representative chemically diverse compounds (not incorporating potency information). In this paper, we propose an integrative clustering approach that makes use of both biological (compound efficacy) and chemical (structural features) data sources for the purpose of discovering a subset of compounds with aligned structural and biological properties. The datasets are integrated at the similarity level by assigning complementary weights to produce a weighted similarity matrix, serving as a generic input in any clustering algorithm. This new analysis work flow is semi-supervised method since, after the determination of clusters, a secondary analysis is performed wherein it finds differentially expressed genes associated to the derived integrated cluster(s) to further explain the compound-induced biological effects inside the cell. In this paper, datasets from two drug development oncology projects are used to illustrate the usefulness of the weighted similarity-based clustering approach to integrate multi-source high-dimensional information to aid drug discovery. Compounds that are structurally and biologically similar to the reference compounds are discovered using this proposed integrative approach. PMID:27312313

  2. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    SciTech Connect

    Cowan-Jacob, Sandra W. Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

  3. Weak affinity chromatography as a new approach for fragment screening in drug discovery.

    PubMed

    Duong-Thi, Minh-Dao; Meiby, Elinor; Bergström, Maria; Fex, Tomas; Isaksson, Roland; Ohlson, Sten

    2011-07-01

    Fragment-based drug design (FBDD) is currently being implemented in drug discovery, creating a demand for developing efficient techniques for fragment screening. Due to the intrinsic weak or transient binding of fragments (mM-μM in dissociation constant (K(D))) to targets, methods must be sensitive enough to accurately detect and quantify an interaction. This study presents weak affinity chromatography (WAC) as an alternative tool for screening of small fragments. The technology was demonstrated by screening of a selected 23-compound fragment collection of documented binders, mostly amidines, using trypsin and thrombin as model target protease proteins. WAC was proven to be a sensitive, robust, and reproducible technique that also provides information about affinity of a fragment in the range of 1 mM-10 μM. Furthermore, it has potential for high throughput as was evidenced by analyzing mixtures in the range of 10 substances by WAC-MS. The accessibility and flexibility of the technology were shown as fragment screening can be performed on standard HPLC equipment. The technology can further be miniaturized and adapted to the requirements of affinity ranges of the fragment library. All these features of WAC make it a potential method in drug discovery for fragment screening. PMID:21352794

  4. New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics

    PubMed Central

    Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

    2013-01-01

    With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development. PMID:23634172

  5. Removing obstacles in neuroscience drug discovery: The future path for animal models

    PubMed Central

    Markou, Athina; Chiamulera, Christian; Geyer, Mark A.; Tricklebank, Mark; Steckler, Thomas

    2009-01-01

    Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, this review critically discusses the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis is placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible. PMID:18830240

  6. Patient-derived stem cells: pathways to drug discovery for brain diseases

    PubMed Central

    Mackay-Sim, Alan

    2013-01-01

    The concept of drug discovery through stem cell biology is based on technological developments whose genesis is now coincident. The first is automated cell microscopy with concurrent advances in image acquisition and analysis, known as high content screening (HCS). The second is patient-derived stem cells for modeling the cell biology of brain diseases. HCS has developed from the requirements of the pharmaceutical industry for high throughput assays to screen thousands of chemical compounds in the search for new drugs. HCS combines new fluorescent probes with automated microscopy and computational power to quantify the effects of compounds on cell functions. Stem cell biology has advanced greatly since the discovery of genetic reprograming of somatic cells into induced pluripotent stem cells (iPSCs). There is now a rush of papers describing their generation from patients with various diseases of the nervous system. Although the majority of these have been genetic diseases, iPSCs have been generated from patients with complex diseases (schizophrenia and sporadic Parkinson’s disease). Some genetic diseases are also modeled in embryonic stem cells (ESCs) generated from blastocysts rejected during in vitro fertilization. Neural stem cells have been isolated from post-mortem brain of Alzheimer’s patients and neural stem cells generated from biopsies of the olfactory organ of patients is another approach. These “olfactory neurosphere-derived” cells demonstrate robust disease-specific phenotypes in patients with schizophrenia and Parkinson’s disease. HCS is already in use to find small molecules for the generation and differentiation of ESCs and iPSCs. The challenges for using stem cells for drug discovery are to develop robust stem cell culture methods that meet the rigorous requirements for repeatable, consistent quantities of defined cell types at the industrial scale necessary for HCS. PMID:23543597

  7. Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery.

    PubMed

    Coutard, Bruno; Decroly, Etienne; Li, Changqing; Sharff, Andrew; Lescar, Julien; Bricogne, Gérard; Barral, Karine

    2014-06-01

    Seasonal and pandemic flaviviruses continue to be leading global health concerns. With the view to help drug discovery against Dengue virus (DENV), a fragment-based experimental approach was applied to identify small molecule ligands targeting two main components of the flavivirus replication complex: the NS3 helicase (Hel) and the NS5 mRNA methyltransferase (MTase) domains. A library of 500 drug-like fragments was first screened by thermal-shift assay (TSA) leading to the identification of 36 and 32 fragment hits binding Hel and MTase from DENV, respectively. In a second stage, we set up a fragment-based X-ray crystallographic screening (FBS-X) in order to provide both validated fragment hits and structural binding information. No fragment hit was confirmed for DENV Hel. In contrast, a total of seven fragments were identified as DENV MTase binders and structures of MTase-fragment hit complexes were solved at resolution at least 2.0Å or better. All fragment hits identified contain either a five- or six-membered aromatic ring or both, and three novel binding sites were located on the MTase. To further characterize the fragment hits identified by TSA and FBS-X, we performed enzymatic assays to assess their inhibition effect on the N7- and 2'-O-MTase enzymatic activities: five of these fragment hits inhibit at least one of the two activities with IC50 ranging from 180μM to 9mM. This work validates the FBS-X strategy for identifying new anti-flaviviral hits targeting MTase, while Hel might not be an amenable target for fragment-based drug discovery (FBDD). This approach proved to be a fast and efficient screening method for FBDD target validation and discovery of starting hits for the development of higher affinity molecules that bind to novel allosteric sites. PMID:24704437

  8. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    PubMed Central

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  9. Genomics in drug discovery: the best things come to those who wait.

    PubMed

    Bansal, Aruna T; Barnes, Michael R

    2008-05-01

    The year 2007 has been marked by the maturation of high-throughput technologies that combine automation and miniaturization to enable systematic surveys of genome sequence variation, gene expression and gene function. These technologies have the potential to affect drug discovery in many ways, from target identification and validation, to pinpointing the molecular variants that influence medicine response. In the current climate of declining pharmaceutical R&D productivity, these approaches offer hope, but a price tag is attached. This review covers exciting advances in the field of genomics, and discusses when to act on genomic data versus when to wait for further information. PMID:18428083

  10. Fragment-Based Drug Discovery in Academia: Experiences From a Tuberculosis Programme

    NASA Astrophysics Data System (ADS)

    Heikkila, Timo J.; Surade, Sachin; Silvestre, Hernani L.; Dias, Marcio V. B.; Ciulli, Alessio; Bromfield, Karen; Scott, Duncan; Howard, Nigel; Wen, Shijun; Wei, Alvin Hung; Osborne, David; Abell, Chris; Blundell, Tom L.

    The problems associated with neglected diseases are often compounded by increasing incidence of antibiotic resistance. Patient negligence and abuse of antibiotics has lead to explosive growth in cases of tuberculosis, with some M. tuberculosis strains becoming virtually untreatable. Structure-based drug development is viewed as cost-effective and time-consuming method for discovery and development of hits to lead compounds. In this review we will discuss the suitability of fragment-based methods for developing new chemotherapeutics against neglected diseases, providing examples from our tuberculosis programme.

  11. Back-up strategies in drug discovery: what, how and when?

    PubMed

    Provins, Laurent; Jnoff, Eric; Genicot, Christophe

    2014-11-01

    The management of back-up strategies in drug discovery and development is usually done on an ad hoc basis depending upon a series of external factors including overall portfolio status and resource and/or budget availability. These are however an essential component of risk management and merit a more structured and systematic conduct throughout the lifetime of a project. An approach based upon a thorough alignment of decision points and data availability as well as a tailor-made progression of various types of back-up program as a function of project categorization is suggested. PMID:25017046

  12. Parasite Mitogen-Activated Protein Kinases as Drug Discovery Targets to Treat Human Protozoan Pathogens

    PubMed Central

    Brumlik, Michael J.; Pandeswara, Srilakshmi; Ludwig, Sara M.; Murthy, Kruthi; Curiel, Tyler J.

    2011-01-01

    Protozoan pathogens are a highly diverse group of unicellular organisms, several of which are significant human pathogens. One group of protozoan pathogens includes obligate intracellular parasites such as agents of malaria, leishmaniasis, babesiosis, and toxoplasmosis. The other group includes extracellular pathogens such as agents of giardiasis and amebiasis. An unfortunate unifying theme for most human protozoan pathogens is that highly effective treatments for them are generally lacking. We will review targeting protozoan mitogen-activated protein kinases (MAPKs) as a novel drug discovery approach towards developing better therapies, focusing on Plasmodia, Leishmania, and Toxoplasma, about which the most is known. PMID:21637385

  13. HCV versus HIV drug discovery: Déjà vu all over again?

    PubMed

    Watkins, William J; Desai, Manoj C

    2013-04-15

    Efforts to address HIV infection have been highly successful, enabling chronic suppression of viral replication with once-daily regimens. More recent research into HCV therapeutics have also resulted in very promising clinical candidates. This Digest explores similarities and differences in the two fields and compares the chronology of drug discovery relative to the availability of enabling tools, and concludes that safe and convenient, once-daily regimens are likely to reach approval much more rapidly for HCV than was the case for HIV. PMID:23489621

  14. Incorporation of rapid thermodynamic data in fragment-based drug discovery.

    PubMed

    Kobe, Akihiro; Caaveiro, Jose M M; Tashiro, Shinya; Kajihara, Daisuke; Kikkawa, Masato; Mitani, Tomoya; Tsumoto, Kouhei

    2013-03-14

    Fragment-based drug discovery (FBDD) has enjoyed increasing popularity in recent years. We introduce SITE (single-injection thermal extinction), a novel thermodynamic methodology that selects high-quality hits early in FBDD. SITE is a fast calorimetric competitive assay suitable for automation that captures the essence of isothermal titration calorimetry but using significantly fewer resources. We describe the principles of SITE and identify a novel family of fragment inhibitors of the enzyme ketosteroid isomerase displaying high values of enthalpic efficiency. PMID:23419007

  15. The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery

    PubMed Central

    2013-01-01

    Background The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans. Results Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates. Conclusions The H. contortus genome and transcriptome provide an essential platform for postgenomic research in this and other important strongylid parasites. PMID:23985316

  16. Latest development in drug discovery on G protein-coupled receptors.

    PubMed

    Lundstrom, Kenneth

    2006-10-01

    G protein-coupled receptors (GPCRs) represent the family of proteins with the highest impact from social, therapeutic and economic point of view. Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as cardiovascular, metabolic, neurodegenerative, psychiatric, cancer and infectious diseases. The classical drug discovery process has relied on screening compounds, which interact favorably with the GPCR of interest followed by further chemical engineering as a mean of improving efficacy and selectivity. In this review, methods for sophisticated chemical library screening procedures will be presented. Furthermore, development of cell-based assays for functional coupling of GPCRs to G proteins will be discussed. Finally, the possibility of applying structure-based drug design will be summarized. This includes the application of bioinformatics knowledge and molecular modeling approaches in drug development programs. The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are presented as a promising future approach for tailor-made drug development. PMID:17073697

  17. Live Cell in Vitro and in Vivo Imaging Applications: Accelerating Drug Discovery

    PubMed Central

    Isherwood, Beverley; Timpson, Paul; McGhee, Ewan J; Anderson, Kurt I; Canel, Marta; Serrels, Alan; Brunton, Valerie G; Carragher, Neil O

    2011-01-01

    Dynamic regulation of specific molecular processes and cellular phenotypes in live cell systems reveal unique insights into cell fate and drug pharmacology that are not gained from traditional fixed endpoint assays. Recent advances in microscopic imaging platform technology combined with the development of novel optical biosensors and sophisticated image analysis solutions have increased the scope of live cell imaging applications in drug discovery. We highlight recent literature examples where live cell imaging has uncovered novel insight into biological mechanism or drug mode-of-action. We survey distinct types of optical biosensors and associated analytical methods for monitoring molecular dynamics, in vitro and in vivo. We describe the recent expansion of live cell imaging into automated target validation and drug screening activities through the development of dedicated brightfield and fluorescence kinetic imaging platforms. We provide specific examples of how temporal profiling of phenotypic response signatures using such kinetic imaging platforms can increase the value of in vitro high-content screening. Finally, we offer a prospective view of how further application and development of live cell imaging technology and reagents can accelerate preclinical lead optimization cycles and enhance the in vitro to in vivo translation of drug candidates. PMID:24310493

  18. Process of Fragment-Based Lead Discovery-A Perspective from NMR.

    PubMed

    Ma, Rongsheng; Wang, Pengchao; Wu, Jihui; Ruan, Ke

    2016-01-01

    Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein-protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein-ligand structure model generation. For weak binders, the initial hit-to-lead evolution can be guided by structural information retrieved from NMR spectroscopy, including chemical shift perturbation, transferred pseudocontact shifts, and paramagnetic relaxation enhancement. This perspective examines structure-guided optimization from weak fragment screening hits to potent leads for challenging PPI targets. PMID:27438813

  19. The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth.

    PubMed

    López-Muñoz, Francisco; Baumeister, Alan A; Hawkins, Mike F; Alamo, Cecilio

    2012-01-01

    The serendipity is the faculty for making a discovery through a combination of accident and sagacity. In psychopharmacology, the serendipity played a key role in the discovery of many psychotropic drugs, although there are marked disputes in this regard, possibly due to semantic differences in relation to the meaning of this term. We have implemented an operational definition of serendipity based on the discovery of something unexpected or not sought intentionally, irrespective of the systematic process leading to the accidental observation. The present paper analyses some representative examples of discoveries in the field of psychopharmacology according to different serendipitous intervention patterns. Following this approach there would be four different imputability patterns: pure serendipitous discoveries (valproic acid/valproate); serendipitous observation leading to a non-serendipitous discoveries (imipramine); non-serendipitous discoveries secondarily associated with serendipitous observation (barbiturates); non-serendipitous discoveries (haloperidol). We can conclude that pure serendipitous discoveries in this field are not very frequent, most common being a mixed pattern; an initial serendipitous observation which leads to a non-serendipitous discovery of clinical utility. This is the case of imipramine, lithium salts, chlorpromazine or meprobamate. PMID:22344494

  20. Academic-Pharma drug discovery alliances: seeking ways to eliminate the valley of death.

    PubMed

    Hammonds, Tim

    2015-01-01

    Industrial pharmaceutical companies (Pharma) share a common goal with academic scientists (Academia) in that they wish to create an environment in which patients are treated for diseases with ever more effective therapies. As disease biology has proven to be ever more complex and money and new drugs are becoming more elusive, Pharma and Academia are reaching toward each other with ever greater collaborative intent. There are a growing number of collaboration models that allow scientists to work together and profit from the creation of new drugs. Here I give a personal view of how we came to where we are, present an overview of a number of these models and look to the future in terms of running successful discovery alliances. PMID:26393391