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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 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

  6. 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

  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 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

  12. 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

  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. 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

  6. 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 ...

  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 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

  10. 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

  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 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

  19. 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

  20. 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

  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. 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

  8. 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

  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. 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

  2. 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

  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. 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

  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. 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

  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. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  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. 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

  13. [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

  14. 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.

  15. 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

  16. 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

  17. 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

  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. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  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. 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

  14. 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

  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. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  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. 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

  11. 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

  12. 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

  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. 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

  18. 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…

  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. 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

  1. 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.

  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