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Journal Cover Drug Discovery Today
  [SJR: 2.084]   [H-I: 130]   [134 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 1359-6446
   Published by Elsevier Homepage  [3089 journals]
  • Contents page 1
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12


      PubDate: 2017-11-29T22:53:08Z
       
  • Contents page 2
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12


      PubDate: 2017-11-29T22:53:08Z
       
  • Do large mergers increase or decrease the productivity of pharmaceutical
           R&D'
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Michael S. Ringel, Michael K. Choy
      There is current uncertainty regarding the effects of mergers on pharmaceutical R&D productivity, with various mechanisms reported by which mergers could either help or harm R&D, and mixed empirical findings in prior analyses. Here, we present an analysis that is novel in several ways: we use downstream measures of R&D productivity, account for both inputs and outputs in our calculations, and use a self-controlled design. We find that recent large pharmaceutical mergers are associated with statistically significant increases in R&D productivity. These results are perhaps not surprising in light of the broader literature on R&D productivity that points to two factors as instrumental in driving higher R&D productivity (depth of scientific information, and objectivity of decision-making based on that information), both of which could be expected to increase because of a merger.

      PubDate: 2017-11-29T22:53:08Z
       
  • Use of a collaborative tool to simplify the outsourcing of preclinical
           safety studies: an insight into the AstraZeneca–Charles River
           Laboratories strategic relationship
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Frederic D.C. Martin, Amanda Benjamin, Ruth MacLean, David M. Hollinshead, Claire Landqvist
      In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies.

      PubDate: 2017-11-29T22:53:08Z
       
  • European regulatory use and impact of subgroup evaluation in marketing
           authorisation applications
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Julien Tanniou, Steven Teerenstra, Sagal Hassan, Andre Elferink, Ingeborg van der Tweel, Christine Gispen-de Wied, Kit C.B. Roes
      Marketing authorisation application dossiers relating to medicinal products containing new active substances and evaluated by the European Medicines Agency (EMA) over the period 2012–2015 were examined. Major objections and other concerns relating to efficacy and safety of the day 80 assessment reports were reviewed. Overall, approved products have more subgroup concerns than nonapproved products, which seems to be a consistent pattern. Subgroup analyses are mainly assessed to have the insurance that subgroups of patients that might lack a positive benefit: risk ratio will not be wrongly included in the approved treatment indication.

      PubDate: 2017-11-29T22:53:08Z
       
  • Tocotrienols: the unsaturated sidekick shifting new paradigms in vitamin E
           therapeutics
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Madhu M. Kanchi, Muthu K. Shanmugam, Grishma Rane, Gautam Sethi, Alan P. Kumar
      Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials. This review provides a comprehensive update on the little-known therapeutic potentials of tocotrienols, which tocopherols lack in a variety of inflammation-driven diseases.
      Vitamin E is a lipid-soluble, radical buster existing in two different isoforms: tocotrienols and tocopherols, and has been used continuously because of its many biological activities, which are pharmacologically capable of tackling a wide array of diseases, thus improving health issues occurring every day.

      PubDate: 2017-11-29T22:53:08Z
       
  • Polypharmacology of conformationally locked methanocarba nucleosides
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Kenneth A. Jacobson, Dilip K. Tosh, Kiran S. Toti, Antonella Ciancetta
      A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.
      Graphical abstract image The scope of action of nucleosides, widely used anticancer and antiviral drugs, is now extended to unconventional targets, including diverse receptors, enzymes and transporters, using a conformational lock.

      PubDate: 2017-11-29T22:53:08Z
       
  • Structural coverage of the proteome for pharmaceutical applications
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Joseph C. Somody, Stephen S. MacKinnon, Andreas Windemuth
      Structure-based computational drug discovery efforts have traditionally focused on the structure of a single, well-known drug target. Important applications, such as target deconvolution and the analysis of polypharmacology, require proteome-scale molecular docking and have been inaccessible to structure-based in silico approaches. One important reason for this inaccessibility was that the structure of most proteins was not known. Lately, this ‘structure gap’ has been closing rapidly, and proteome-scale molecular docking seems within reach. Here, we survey the current state of structural coverage of the human genome and find that coverage is truly proteome-wide, both overall and in most pharmaceutically relevant categories of proteins. The time is right for structure-based approaches to target deconvolution and polypharmacology.

      PubDate: 2017-11-29T22:53:08Z
       
  • Uncovering novel repositioning opportunities using the Open Targets
           platform
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Mugdha Khaladkar, Gautier Koscielny, Samiul Hasan, Pankaj Agarwal, Ian Dunham, Deepak Rajpal, Philippe Sanseau
      The recently developed Open Targets platform consolidates a wide range of comprehensive evidence associating known and potential drug targets with human diseases. We have harnessed the integrated data from this platform for novel drug repositioning opportunities. Our computational workflow systematically mines data from various evidence categories and presents potential repositioning opportunities for drugs that are marketed or being investigated in ongoing human clinical trials, based on evidence strength on target–disease pairing. We classified these novel target–disease opportunities in several ways: (i) number of independent counts of evidence; (ii) broad therapy area of origin; and (iii) repositioning within or across therapy areas. Finally, we elaborate on one example that was identified by this approach.

      PubDate: 2017-11-29T22:53:08Z
       
  • Label-free technology and patient cells: from early drug development to
           precision medicine
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Julia M. Hillger, Wai-Ling Lieuw, Laura H. Heitman, Adriaan P. IJzerman
      Drug development requires physiologically more appropriate model systems and assays to increase understanding of drug action and pathological processes in individual humans. Specifically, patient-derived cells offer great opportunities as representative cellular model systems. Moreover, with novel label-free cellular assays, it is often possible to investigate complex biological processes in their native environment. Combining these two offers distinct opportunities for increasing physiological relevance. Here, we review impedance-based label-free technologies in the context of patient samples, focusing on commonly used cell types, including fibroblasts, blood components, and stem cells. Applications extend as far as tissue-on-a-chip models. Thus, applying label-free technologies to patient samples can produce highly biorelevant data and, with them, unique opportunities for drug development and precision medicine.
      Graphical abstract image

      PubDate: 2017-11-29T22:53:08Z
       
  • RanBPM: a potential therapeutic target for modulating diverse
           physiological disorders
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Soumyadip Das, Bharathi Suresh, Hyongbum (Henry) Kim, Suresh Ramakrishna
      The Ran-binding protein microtubule-organizing center (RanBPM) is a highly conserved nucleocytoplasmic protein involved in a variety of intracellular signaling pathways that control diverse cellular functions. RanBPM interacts with proteins that are linked to various diseases, including Alzheimer’s disease (AD), schizophrenia (SCZ), and cancer. In this article, we define the characteristics of the scaffolding protein RanBPM and focus on its interaction partners in diverse physiological disorders, such as neurological diseases, fertility disorders, and cancer.

      PubDate: 2017-11-29T22:53:08Z
       
  • Zinc oxide nanoparticles: a promising nanomaterial for biomedical
           applications
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Pawan K. Mishra, Harshita Mishra, Adam Ekielski, Sushama Talegaonkar, Bhuvaneshwar Vaidya
      Zinc oxide (ZnO) nanoparticles (NPs) are a promising platform for use in biomedical research, especially given their anticancer and antimicrobial activities. These activities are associated with the ability of ZnO NPs to generate reactive oxygen species (ROS) and induce apoptosis. In addition, ZnO NPs have been successfully exploited as drug carriers for loading and transporting drugs to target sites, thereby reducing unwanted toxicity and off-target effects, and resulting in amplified synergistic effects. Here, we discuss the synthesis and biomedical applications of ZnO NPs.

      PubDate: 2017-11-29T22:53:08Z
       
  • Near infra red spectroscopy: a tool for solid state characterization
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Rahul B. Chavan, Nallamothu Bhargavi, Anurag Lodagekar, Nalini R. Shastri
      Physical characterization of solid form of drug is of paramount importance as its biopharmaceutical properties and/or its processing behavior may be altered. Early identification and monitoring of solid state transformation is a critical requirement for pharmaceutical product development. In combination with chemometrics, a non destructive and non invasive technique like NIR is a powerful tool for solid state characterization. Main focus of this review is application of NIR for qualitative and quantitative analysis of solid forms of drugs and excipients. In addition, this review also sheds light on recent advancement in NIR, such as NIR chemical imaging and NIR based hyphenated techniques.

      PubDate: 2017-11-29T22:53:08Z
       
  • High-throughput flow cytometry for drug discovery: principles,
           applications, and case studies
    • Abstract: Publication date: December 2017
      Source:Drug Discovery Today, Volume 22, Issue 12
      Author(s): Mei Ding, Karin Kaspersson, David Murray, Catherine Bardelle
      Flow cytometry is a technology providing multiparametric analysis of single cells or other suspension particles. High-throughput (HT) flow cytometry has become an attractive screening platform for drug discovery. In this review, we highlight the recent HT flow cytometry applications, and then focus on HT flow cytometry deployment at AstraZeneca (AZ). Practical considerations for successful HT flow cytometry assay development and screening are provided based on experience from four project case studies at AZ. We provide an overview of the scientific rationale, explain why HT flow cytometry was chosen and how HT flow cytometry assays deliver new ways to support the drug discovery process.

      PubDate: 2017-11-29T22:53:08Z
       
  • One-size-fits-all dosing in oncology wastes money, innovation and lives
    • Abstract: Publication date: Available online 21 November 2017
      Source:Drug Discovery Today
      Author(s): David C. Norris


      PubDate: 2017-11-29T22:53:08Z
       
  • Understanding missing proteins: a functional perspective
    • Abstract: Publication date: Available online 20 November 2017
      Source:Drug Discovery Today
      Author(s): Longjian Zhou, Limsoon Wong, Wilson Wen Bin Goh
      A missing protein (MP) is an unconfirmed genetic sequence for which a protein product is not yet detected. Currently, MPs are tiered based on supporting evidence mainly in the form of protein existence (PE) classification. As we discuss here, this definition is overly restrictive because proteins go missing in day-to-day proteomics as a result of low abundance, lack of sequence specificity, splice variants, and so on. Thus, we propose a broader functional classification of MPs that complements PE classification, discuss major causes, and examine three corresponding solution tiers: biological, technical, and informatics. We assert that informatics-driven solutions would have a major role in resolving the MP problem (MPP).

      PubDate: 2017-11-29T22:53:08Z
       
  • Recent advances in bacteriophage-based methods for bacteria detection
    • Abstract: Publication date: Available online 20 November 2017
      Source:Drug Discovery Today
      Author(s): Łukasz Richter, Marta Janczuk-Richter, Joanna Niedziółka-Jönsson, Jan Paczesny, Robert Hołyst
      Fast and reliable bacteria detection is crucial for lowering the socioeconomic burden related to bacterial infections (e.g., in healthcare, industry or security). Bacteriophages (i.e., viruses with bacterial hosts) pose advantages such as great specificity, robustness, toughness and cheap preparation, making them popular biorecognition elements in biosensors and other assays for bacteria detection. There are several possible designs of bacteriophage-based biosensors. Here, we focus on developments based on whole virions as recognition agents. We divide the review into sections dealing with phage lysis as an analytical signal, phages as capturing elements in assays and phage-based sensing layers, putting the main focus on development reported within the past three years but without omitting the fundamentals.
      Graphical abstract image

      PubDate: 2017-11-29T22:53:08Z
       
  • Applications of stimuli-responsive nanoscale drug delivery systems in
           translational research
    • Abstract: Publication date: Available online 16 November 2017
      Source:Drug Discovery Today
      Author(s): Mengjie Gu, Xin Wang, Tan Boon Toh, Edward Kai-Hua Chow
      Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside.

      PubDate: 2017-11-29T22:53:08Z
       
  • The role of fMRI in drug development
    • Abstract: Publication date: Available online 15 November 2017
      Source:Drug Discovery Today
      Author(s): Owen Carmichael, Adam J. Schwarz, Christopher H. Chatham, David Scott, Jessica A. Turner, Jaymin Upadhyay, Alexandre Coimbra, James A. Goodman, Richard Baumgartner, Brett A. English, John W. Apolzan, Preetham Shankapal, Keely R. Hawkins
      Functional magnetic resonance imaging (fMRI) has been known for over a decade to have the potential to greatly enhance the process of developing novel therapeutic drugs for prevalent health conditions. However, the use of fMRI in drug development continues to be relatively limited because of a variety of technical, biological, and strategic barriers that continue to limit progress. Here, we briefly review the roles that fMRI can have in the drug development process and the requirements it must meet to be useful in this setting. We then provide an update on our current understanding of the strengths and limitations of fMRI as a tool for drug developers and recommend activities to enhance its utility.
      Brain fMRI has the potential to become a powerful tool for clinical trials but is currently underutilized. Here, we explain why and present a path forward.

      PubDate: 2017-11-18T03:29:43Z
       
  • Personalized nanomedicine for CNS diseases
    • Abstract: Publication date: Available online 15 November 2017
      Source:Drug Discovery Today
      Author(s): Ajeet Kaushik, Rahul Dev Jayant, Vinay Bhardwaj, Madhavan Nair
      Central nervous system (CNS) diseases are rapidly increasing globally. Currently used therapeutic agents to treat CNS diseases exhibit significant efficacy. However, the inability of these drugs to cross the blood–brain barrier (BBB) and invasiveness of the technologies to achieve localized drug delivery in disease-specific parts of the brain have thwarted pain-free and complete treatment of CNS diseases. Therefore, the safe, non-invasive, and targeted delivery of drugs to the brain using nanoparticles (NPs) is currently receiving considerable research attention. Here, we highlight advances in state-of-the-art personalized nanomedicine for the treatment of CNS diseases (with a focus on dementia), the related challenges, possible solutions, and prospects for nano-enabled personalized medicine.

      PubDate: 2017-11-18T03:29:43Z
       
  • Drug Discovery Tomorrow: How to Catapult Ourselves into the Future
    • Abstract: Publication date: Available online 14 November 2017
      Source:Drug Discovery Today
      Author(s): Chris Molloy


      PubDate: 2017-11-18T03:29:43Z
       
  • Fixed-dose combinations: a potential means to boost drug development for
           selected drugs
    • Abstract: Publication date: Available online 14 November 2017
      Source:Drug Discovery Today
      Author(s): Charles Oo, Sherwin K.B. Sy


      PubDate: 2017-11-18T03:29:43Z
       
  • Nanomedicine safety in preclinical and clinical development: focus on
           idiosyncratic injection/infusion reactions
    • Abstract: Publication date: Available online 13 November 2017
      Source:Drug Discovery Today
      Author(s): S.M. Moghimi
      Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related ‘pseudoallergy’, where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered. However, the second hypothesis (the rapid phagocytic response hypothesis) states a transitional link from robust clearance of nanoparticles (NPs) from the blood by strategically placed responsive macrophages to adverse hemodynamic and cardiopulmonary reactions, regardless of complement activation. Here, I critically examine and discuss these hypotheses. Current experimentally derived evidence appears to be more in support of the rapid phagocytic response hypothesis than of the pseudoallergy hypothesis.
      This article critically discusses the role of complement system and phagocytic cells in the initiation of adverse injection reactions to particulate drug carriers, contrast agents, and nanopharmaceuticals.

      PubDate: 2017-11-18T03:29:43Z
       
  • Galectin-3: mediator of microglia responses in injured brain
    • Abstract: Publication date: Available online 10 November 2017
      Source:Drug Discovery Today
      Author(s): Reza Rahimian, Louis-Charles Béland, Jasna Kriz
      Galectin-3 is a pleiotropic protein involved in cell activation, proliferation and migration and plays a pivotal part as an inflammatory mediator in neurodegeneration. Galectin-3 is associated with microglial activation and proliferation after ischemia. Given its putative role as a dynamic fine-tuner of microglia, activation of Galectin-3 provides molecular cues in design of new immunomodulatory strategies for stroke management. This review summarizes recent evidence on the role of Galectin-3 as a mediator of immune responses in damaged brain and mechanisms employed by Galectin-3 to affect microglial function.

      PubDate: 2017-11-18T03:29:43Z
       
  • Contents page 1
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11


      PubDate: 2017-11-18T03:29:43Z
       
  • Contents page 2
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11


      PubDate: 2017-11-18T03:29:43Z
       
  • 2016 in review: FDA approvals of new molecular entities
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Rebekah H. Griesenauer, Michael S. Kinch
      An overview of drugs approved by FDA in 2016 reveals dramatic disruptions in long-term trends. The number of new molecular entities (NMEs) dropped, reflecting the lowest rate of small-molecule approvals observed in almost five decades. In addition, the pace of industry consolidation slowed substantially. The impact of mergers and acquisitions decreased the total number of organizations with past approval experience and continued research and development (R&D) activities to 102, divided evenly between more established pharmaceutical and newer biotechnology companies. Despite these substantial differences, the industry continued to pursue regulatory incentives, as evidenced by a continued increase in the fraction of NMEs approved using an orphan or priority designation, and almost all oncology drugs approved in 2016 utilized these mechanisms.

      PubDate: 2017-11-18T03:29:43Z
       
  • Emerging technologies for prediction of drug candidate efficacy in the
           preclinical pipeline
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Denis Menshykau
      The pharmaceutical industry is tackling increasingly complex multifactorial diseases, resulting in increases in research & development (R&D) costs and reductions in the success rates for drug candidates during Phase 2 and 3 clinical trials, with a lack of efficacy being the primary reason for drug candidate failure. This implies that the predictive power of current preclinical assays for drug candidate efficacy is suboptimal and, therefore, that alternatives should be developed. Here, I review emerging in vitro, imaging, and in silico technologies and discuss their potential contribution to drug efficacy assessment. Importantly, these technologies are complimentary and can be bundled into the preclinical platform. In particular, patient-on-a-chip recapitulates both human genetics and physiology. The response of a patient-on-a-chip to drug candidate treatment is monitored with light-sheet fluorescent microscopy and fed into the image-analysis pipeline to reconstruct an image-based systems-level model for disease pathophysiology and drug candidate mode of action. Thus, such models could be useful tools for assessing drug candidate efficacy and safety in humans.

      PubDate: 2017-11-18T03:29:43Z
       
  • Mechanistic applications of click chemistry for pharmaceutical drug
           discovery and drug delivery
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Nilesh M. Meghani, Hardik H. Amin, Beom-Jin Lee
      The concept of click chemistry (CC), first introduced by K.B. Sharpless, has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), polymer chemistry, and material sciences. In this review, we outline novel aspects of CC related to drug discovery and drug delivery, with a brief overview of molecular mechanisms underlying each click reaction commonly used by researchers, and the main patents that paved the way for further diverse medicinal applications. We also describe recent progress in drug discovery and polymeric and carbon material-based drug delivery for potential pharmaceutical applications and advancements based on the CC approach, and discuss some intrinsic limitations of this popular conjugation reaction. The use of CC is likely to significantly advance drug discovery and bioconjugation development.
      Graphical abstract image Click chemistry is set to develop new potential molecules and biomaterials for treatment of various diseases, drug delivery and diagnostics, respectively.

      PubDate: 2017-11-18T03:29:43Z
       
  • Molecular epigenetic targets for liver diseases: current challenges and
           future prospects
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Robert Zeidler, Bruno Leonardo de Freitas Soares, Augustinus Bader, Shibashish Giri
      Advanced chemotherapy fails to treat liver cancer but recent progress in understanding epigenetic modifications have witnessed promising clinical outcomes. Epigenetic alteration is the alteration of epigenomes (surrounding histone proteins) without changing the DNA sequence. Such epigenetic mechanisms include histone modifications such as methylation, acetylation, phosphorylation and sumoylation followed by changes in the genomic architecture. Current studies involving the understanding of small RNA molecules such as noncoding RNA and microRNA in modulating the chromatin architecture are explained in depth here, along with effects of some novel compounds from recent preclinical and clinical evidence. This review also discusses the current state-of-the-art strategies and the possible scope of investigation to improve the existing treatment methods for liver-related disorders.
      Graphical abstract image This paper is a demonstration of the potential of epigenetic approaches that will inevitably begin to move into more clinical trials for use in patients with liver diseases including hepatocellular carcinoma.

      PubDate: 2017-11-18T03:29:43Z
       
  • The Warburg effect and glucose-derived cancer theranostics
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Rakesh K. Tekade, Xiankai Sun
      Tumor cells are known for their propensity to proliferate uncontrollably and generate multitudes of metastatic masses at the advanced stages of cancer. During this progression, tumor cells switch their energy source from mitochondrial oxidative phosphorylation to a glucose-dependent glycolytic pathway, despite the availability of oxygen. Consequently, tumor cells increase their metabolic rates as well as glucose uptake to maintain their proliferation. This atypical metabolic phenomenon is known as the Warburg effect, which has been recognized as a hallmark of cancer and serves as a promising target for diagnosis and therapy of cancer. In this review, we summarize the current advances toward the development of glucose-derived therapeutic and diagnostic agents (theranostics) of cancer.
      Graphical abstract image The Warburg effect is a well-recognized hallmark of cancer that serves as a promising target for the development of therapeutic and diagnostic (theranostic) agents for cancer. Here, we summarize the current advances in this field.

      PubDate: 2017-11-18T03:29:43Z
       
  • Microfluidic technologies for anticancer drug studies
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Karolina P. Valente, Sultan Khetani, Ahmad R. Kolahchi, Amir Sanati-Nezhad, Afzal Suleman, Mohsen Akbari
      The study of cancer growth mechanisms and the determination of the efficacy of experimental therapeutics are usually performed in two-dimensional (2D) cell culture models. However, these models are incapable of mimicking complex interactions between cancer cells and the environment. With the advent of microfluidic technologies, the combination of multiple cell cultures with mechanical and biochemical stimuli has enabled a better recapitulation of the three-dimensional (3D) tumor environment using minute amounts of reagents. These models can also be used to study drug transport, hypoxia, and interstitial pressure within the tumor. In this review, we highlight the applications of microfluidic-based models in anticancer drug studies and provide a perspective on the future of the clinical applications of microfluidic systems for anticancer drug development.
      Microfluidic technology offers an excellent alternative for current in vitro models. This review examines the impact of microfluidic systems on chemotherapeutic studies as a basis for diminishing the gap between in vivo and in vitro models.

      PubDate: 2017-11-18T03:29:43Z
       
  • Aged macular degeneration: current therapeutics for management and
           promising new drug candidates
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Afrah Jalil Abd, Rupinder K. Kanwar, Jagat R. Kanwar
      In elderly aged related macular degeneration (AMD) is the common eye disease which impairs the vision and most of the time it creates permanent vision loss. Because elderly population constitute the larger percentage among society, visual loss due to AMD has become a growing problem. Despite the advances made in developing therapeutics, there is still no satisfactory treatment. The limitations of the available treatments are due to the absence of potent, non-invasive therapy. Furthermore, part of the available drugs targets angiogenesis and create a hypoxic environment that augment further angiogenesis. Therefore, it is reasonable to consider eye integrity and the correlation between hypoxia and angiogenesis before developing successful drugs. This review highlighted issues regarding the available therapeutic strategies and explored whether AMD can be managed by employing specific nanoformulations.

      PubDate: 2017-11-18T03:29:43Z
       
  • From machine learning to deep learning: progress in machine intelligence
           for rational drug discovery
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Lu Zhang, Jianjun Tan, Dan Han, Hao Zhu
      Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure–activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply. However, when drug discovery moved into the era of ‘big’ data, machine learning approaches evolved into deep learning approaches, which are a more powerful and efficient way to deal with the massive amounts of data generated from modern drug discovery approaches. Here, we summarize the history of machine learning and provide insight into recently developed deep learning approaches and their applications in rational drug discovery. We suggest that this evolution of machine intelligence now provides a guide for early-stage drug design and discovery in the current big data era.

      PubDate: 2017-11-18T03:29:43Z
       
  • Switching off CD73: a way to boost the activity of conventional and
           targeted antineoplastic therapies
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Luca Antonioli, Sergey V. Novitskiy, Kris F. Sachsenmeier, Matteo Fornai, Corrado Blandizzi, György Haskó
      Over the past few years, several preclinical studies have highlighted the value of CD73 (ecto-5′-nucleotidase) as a potential therapeutic target for cancer therapy. Indeed, the pharmacological blockade of CD73, via monoclonal antibodies or small molecules, has promise in counteracting cancer development, growth and spread. Synergistic combinations of anti-CD73 drugs with conventional cancer treatments (i.e., chemotherapy, radiation therapy, immunotherapy, targeted therapy) have increased therapeutic potential. In this review, we discuss the potential synergistic effects of CD73 blockers and conventional antineoplastic therapies in the treatment of cancer.

      PubDate: 2017-11-18T03:29:43Z
       
  • A comprehensive review on polyelectrolyte complexes
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Venkata S. Meka, Manprit K.G. Sing, Mallikarjuna R. Pichika, Srinivasa R. Nali, Venkata R.M. Kolapalli, Prashant Kesharwani
      Global research on polyelectrolytes at a fundamental and applied level is intensifying because the advantages of sustainability are being accepted in academia and industrial research settings. During recent decades, polyelectrolytes became one of the most attractive subjects of scientific research owing to their great potential in the areas of advanced technologies. Polyelectrolytes are a type of polymer that have multitudinous ionizable functional groups. Ionized polyelectrolytes in solution can form a complex with oppositely charged polyelectrolytes — a polyelectrolyte complex (PEC). The present article provides a comprehensive review on PECs and their classification, theory and characterization, as well as a critical analysis of the current research.

      PubDate: 2017-11-18T03:29:43Z
       
  • Mouse models of nonalcoholic steatohepatitis in preclinical drug
           development
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Henrik H. Hansen, Michael Feigh, Sanne S. Veidal, Kristoffer T. Rigbolt, Niels Vrang, Keld Fosgerau
      Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH. Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery.

      PubDate: 2017-11-18T03:29:43Z
       
  • Mu-Opioid receptor biased ligands: A safer and painless discovery of
           analgesics'
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Abraham Madariaga-Mazón, Andrés F. Marmolejo-Valencia, Yangmei Li, Lawrence Toll, Richard A. Houghten, Karina Martinez-Mayorga
      Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand–receptor recognition process.

      PubDate: 2017-11-18T03:29:43Z
       
  • Stem cells in cardiovascular diseases: turning bad days into good ones
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Maira Souza de Oliveira, Felipe Saldanha-Araujo, Alfredo Miranda de Goes, Fabricio F. Costa, Juliana Lott de Carvalho
      During the past decade, several types of stem cells have been investigated as promising therapeutic agents for cardiovascular diseases (CVDs). Among them, mesenchymal stem cells (MSCs) were the most investigated stem cell population. Hundreds of clinical trials later, results remain disappointing and far from the revolutionary improvements expected for heart function. In the present review, we address strategies under investigation to boost MSC therapy for CVDs. Pluripotent stem cells (PSCs) are also intended to reach clinical applications for CVDs, but here we suggest that, in the short term, the major impact of PSCs in the cardiovascular field might be at the bench and not the bedside.

      PubDate: 2017-11-18T03:29:43Z
       
  • Myotonic dystrophy: candidate small molecule therapeutics
    • Abstract: Publication date: November 2017
      Source:Drug Discovery Today, Volume 22, Issue 11
      Author(s): Piotr Konieczny, Estela Selma-Soriano, Anna S. Rapisarda, Juan M. Fernandez-Costa, Manuel Perez-Alonso, Ruben Artero
      Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing, and therapeutic gene modulation.

      PubDate: 2017-11-18T03:29:43Z
       
  • Recent advances in galactose-engineered nanocarriers for the site-specific
           delivery of siRNA and anticancer drugs
    • Abstract: Publication date: Available online 10 November 2017
      Source:Drug Discovery Today
      Author(s): Ashay Jain, Atul Jain, Prahlad Parajuli, Vijay Mishra, Gargi Ghoshal, Bhupinder Singh, Uma Shankar Shivhare, Om Prakash Katare, Prashant Kesharwani
      Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand–receptor-mediated delivery of drug carriers.
      Galactose-functionalized nanocarriers open new avenues for the design of highly effective multifunctional, targeted drug delivery systems.

      PubDate: 2017-11-10T13:23:28Z
       
  • Rare genetic diseases: update on diagnosis, treatment and online resources
    • Abstract: Publication date: Available online 10 November 2017
      Source:Drug Discovery Today
      Author(s): Robert E. Pogue, Denise P. Cavalcanti, Shreya Shanker, Rosangela V. Andrade, Lana R. Aguiar, Juliana L.de Carvalho, Fabrício F. Costa
      Rare genetic diseases collectively impact a significant portion of the world’s population. For many diseases there is limited information available, and clinicians can find difficulty in differentiating between clinically similar conditions. This leads to problems in genetic counseling and patient treatment. The biomedical market is affected because pharmaceutical and biotechnology industries do not see advantages in addressing rare disease treatments, or because the cost of the treatments is too high. By contrast, technological advances including DNA sequencing and analysis, together with computer-aided tools and online resources, are allowing a more thorough understanding of rare disorders. Here, we discuss how a collection of various types of information together with the use of new technologies is facilitating diagnosis and, consequently, treatment of rare diseases.

      PubDate: 2017-11-10T13:23:28Z
       
  • Mesoporous silica nanoparticles: a smart nanosystem for management of
           breast cancer
    • Abstract: Publication date: Available online 8 November 2017
      Source:Drug Discovery Today
      Author(s): Neelam Poonia, Viney Lather, Deepti Pandita
      Breast cancer is the second-leading cause of death in women worldwide owing to aggressive metastasis, lack of early diagnosis and poor access to treatment amenities. During the past decade, mesoporous silica nanoparticles (MSNs) have gained ground for the delivery of a wide variety of chemotherapeutic and bioimaging agents owing to their unique characteristics and straightforward fabrication methods. Present research studies based on MSNs have provided various potential insights in their applicability in breast cancer treatment by improving solubility and stability and decreasing the adverse effects of current treatment regimens. This review focuses on the applicability of this novel modality in the management of breast cancer.
      Inorganic nanoparticles paving the way for better management of breast cancer.

      PubDate: 2017-11-10T13:23:28Z
       
  • Fishing anti(lymph)angiogenic drugs with zebrafish
    • Abstract: Publication date: Available online 31 October 2017
      Source:Drug Discovery Today
      Author(s): Melissa García-Caballero, Ana R. Quesada, Miguel A. Medina, Manuel Marí-Beffa
      Zebrafish, an amenable small teleost fish with a complex mammal-like circulatory system, is being increasingly used for drug screening and toxicity studies. It combines the biological complexity of in vivo models with a higher-throughput screening capability compared with other available animal models. Externally growing, transparent embryos, displaying well-defined blood and lymphatic vessels, allow the inexpensive, rapid, and automatable evaluation of drug candidates that are able to inhibit neovascularisation. Here, we briefly review zebrafish as a model for the screening of anti(lymph)angiogenic drugs, with emphasis on the advantages and limitations of the different zebrafish-based in vivo assays.

      PubDate: 2017-11-03T14:00:05Z
       
  • Interfering peptides targeting protein–protein interactions: the
           next generation of drugs'
    • Abstract: Publication date: Available online 31 October 2017
      Source:Drug Discovery Today
      Author(s): Heriberto Bruzzoni-Giovanelli, Valerie Alezra, Nicolas Wolff, Chang-Zhi Dong, Pierre Tuffery, Angelita Rebollo
      Protein–protein interactions (PPIs) are well recognized as promising therapeutic targets. Consequently, interfering peptides (IPs) – natural or synthetic peptides capable of interfering with PPIs – are receiving increasing attention. Given their physicochemical characteristics, IPs seem better suited than small molecules to interfere with the large surfaces implicated in PPIs. Progress on peptide administration, stability, biodelivery and safety are also encouraging the interest in peptide drug development. The concept of an IP has been validated for several PPIs, generating great expectations for their therapeutic potential. Here, we describe approaches and methods useful for IP identification and in silico, physicochemical and biological-based strategies for their design and optimization. Selected promising in-vivo-validated examples are described and advantages, limitations and potential of IPs as therapeutic tools are discussed.
      Today, by improving administration, stability and intracellular delivery, the interest in peptides as potential drugs is resurgent, especially for targeting the thousands of intracellular protein–protein interactions implicated in cellular homeostasis and pathological conditions

      PubDate: 2017-11-03T14:00:05Z
       
  • What is precise pathophysiology in development of hypertension in
           pregnancy' Precision medicine requires precise physiology and
           pathophysiology
    • Abstract: Publication date: Available online 31 October 2017
      Source:Drug Discovery Today
      Author(s): Qinqin Gao, Jiaqi Tang, Na Li, Bailin Liu, Mengshu Zhang, Miao Sun, Zhice Xu
      It is widely accepted that placental ischemia is central in the evolution of hypertension in pregnancy. Many studies and reviews have targeted placental ischemia to explain mechanisms for initiating pregnancy hypertension. The placenta is rich in blood vessels, which are the basis for developing placental ischemia. However, is the physiology of placental vessels the same as that of nonplacental vessels' What is the pathophysiology of placental vessels in development of pregnancy hypertension' This review aims to provide a comprehensive summary of special features of placental vascular regulations and the pathophysiological changes linked to preeclamptic conditions. Interestingly, some popular theories or accepted concepts could be based on our limited knowledge and evidence regarding placental vascular physiology, pharmacology and pathophysiology. New views raised could offer interesting ideas for future investigation of mechanisms as well as targets for pregnancy hypertension.
      Special physiology and precise pathophysiology in placental vessels are crucial in understanding mechanisms of pregnant hypertension and the basis for precision medicine targeting preeclampsia.

      PubDate: 2017-11-03T14:00:05Z
       
  • NCp7: targeting a multitasking protein for next-generation anti-HIV drug
           development: covalent inhibitors
    • Abstract: Publication date: Available online 28 October 2017
      Source:Drug Discovery Today
      Author(s): Luca Sancineto, Nunzio Iraci, Oriana Tabarrini, Claudio Santi
      The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad-spectrum agents that are less prone to select for resistant strains. Here, we provide a comprehensive overview of the covalent NCp7 inhibitors that have emerged over the past 25 years of drug discovery campaigns, emphasising, where possible, their structure–activity relationships (SARs) and pharmacophoric features.
      Twenty years of drug discovery campaigns devoted to the identification of NCp7 covalent inhibitors are herein exhaustively reviewed from a medicinal chemistry perspective.

      PubDate: 2017-11-03T14:00:05Z
       
  • Current attempts to implement microRNA-based diagnostics and therapy in
           cardiovascular and metabolic disease: a promising future
    • Abstract: Publication date: Available online 28 October 2017
      Source:Drug Discovery Today
      Author(s): Punniyakoti V. Thanikachalam, Srinivasan Ramamurthy, Zheng W. Wong, Koo B. Jin, Wong J. Ying, Mohd F.B. Abdullah, Chin Y. Haur, Chia C. Hou, Tan J. Yi, Neo W. Ting, Tan B. Sen, Khan W. Fang, Prashant Kesharwani
      MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression at the post-translational level. miRNA-based therapeutic agents are important because of the functionality of miRNAs in regulating lipid and glucose metabolism and their role in the pathogenesis of metabolic disorders such as diabetes and obesity, where dysregulation leads to disease; they are also important in angiogenesis. miRNAs additionally serve as biomarkers in the diagnosis, prognosis and risk assessment of disease and in monitoring the response to treatment. Here, we provide a brief overview of progress in miRNA-based therapeutics in the preclinical and clinical setting and highlight the novel outcomes and opportunities in the diagnosis and treatment of metabolic conditions. In addition, we present the role of miRNAs in stem cell therapy which could have great potential in regenerative medicine.

      PubDate: 2017-11-03T14:00:05Z
       
  • Alternative fluorophores designed for advanced molecular imaging
    • Abstract: Publication date: Available online 27 October 2017
      Source:Drug Discovery Today
      Author(s): Lara G. Freidus, Priyamvada Pradeep, Pradeep Kumar, Yahya E. Choonara, Viness Pillay
      Fluorescent molecular imaging has advanced drastically over the last decade. With the development of high resolution microscopy techniques and the ability to visualize intracellular molecular events, there is a growing need for new fluorophores to accompany these fast-developing techniques. Therefore, there has been the substantial development of alternative fluorophores for single molecule detection and molecular imaging. These rationally designed fluorophores have infinite possibilities and novel fluorophores are constantly being produced for different applications. This review focused on the recent developments in novel fluorophores designed for molecular imaging and single molecule detection. Here within, single molecule imaging, smart fluorescent probes, two photon microscopy, Förster resonance energy transfer (FRET), and super resolution microscopy are discussed in detail.
      Graphical abstract image A wide variety of alternative and novel fluorophores have been developed with wide-reaching applications in the fields of single molecule detection and molecular imaging.

      PubDate: 2017-11-03T14:00:05Z
       
  • The ambivalent place of ethics in European regulatory documents
    • Abstract: Publication date: Available online 27 October 2017
      Source:Drug Discovery Today
      Author(s): R.D.L.C. Bernabe, G.J.M.W. van Thiel, C.C. Gispen, N.S. Breekveldt, J.J.M. van Delden


      PubDate: 2017-11-03T14:00:05Z
       
 
 
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