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Drug Discovery Today
Journal Prestige (SJR): 2.008
Citation Impact (citeScore): 6
Number of Followers: 138  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 1359-6446
Published by Elsevier Homepage  [3163 journals]
  • Polycomb repressive complex 2 inhibitors: emerging epigenetic modulators
    • Abstract: Publication date: Available online 19 July 2018Source: Drug Discovery TodayAuthor(s): Danish Uddin, Naidu Subbarao, Mohammad Faheem, Shahper Nazir KhanPolycomb repressive complex 2 (PRC2) plays a significant part in histone methylation − trimethylating K27 at H3, an epigenetic hallmark of gene silencing. Inhibition of PRC2 has been reported as a promising strategy for the treatment of various cancers. Significant efforts have been made toward the development of PRC2 inhibitors and some of them have progressed to clinical trials. The binding mode of these inhibitors is well understood. Here, we summarize the advances in drug discovery and development for PRC2 component inhibitors by focusing on their chemotypes, activity, selectivity and binding modes. We believe that such analysis will provide new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.
       
  • How soon will digital endpoints become a cornerstone for future drug
           development'
    • Abstract: Publication date: Available online 17 July 2018Source: Drug Discovery TodayAuthor(s): Philip Boehme, Arne Hansen, Ronenn Roubenoff, Joseph Scheeren, Maximilian Herrmann, Thomas Mondritzki, Jan Ehlers, Hubert TruebelDigital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic–industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems.
       
  • Contents page 1
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s):
       
  • Computational modeling approaches to quantitative structure–binding
           kinetics relationships in drug discovery
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Pier G. De Benedetti, Francesca FanelliSimple comparative correlation analyses and quantitative structure–kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug–target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling.
       
  • The neuroprotective role of the brain opioid system in stroke injury
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Bhuvaneshwar Vaidya, Ali Ehsan Sifat, Vardan T. Karamyan, Thomas J. AbbruscatoNovel neuroprotective therapies are desperately needed to improve neuronal recovery after ischemic stroke and extend the therapeutic window or offset some of the adverse effects of tissue-type plasminogen activator (tPA). These advances could provide a more effective and safe therapeutic regimen for patients with ischemic stroke. The opioid system has gained intense interest over the past few years and is currently being investigated as a viable target for the pharmacological treatment of stroke. In this review, we focus on different opioid receptors (ORs) and their distribution in the central nervous system (CNS), and the effect of ischemic stroke on their redistribution. We also discuss studies involving the use of the selective and nonselective and/or simultaneous targeting of ORs for neuroprotection during ischemic stroke.
       
  • Can we accelerate medicinal chemistry by augmenting the chemist with Big
           Data and artificial intelligence'
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Edward J. Griffen, Alexander G. Dossetter, Andrew G. Leach, Shane Montague
       
  • Prediction of brain:blood unbound concentration ratios in CNS drug
           discovery employing in silico and in vitro model systems
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Houfu Liu, Kelly Dong, Wandong Zhang, Scott G. Summerfield, Georg C. TerstappenRecent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (Kp,uu,br) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the Kp,uu,br of discovery compounds with special emphasis on the in-vitro–in-vivo correlation. We also discuss clinical ‘translation’ of rodent Kp,uu,br and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico Kp,uu,br models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood–brain barrier transporters and their in vivo relevance aside from P-gp and BCRP.Graphical abstractGraphical abstract for this article
       
  • A tumor multicomponent targeting chemoimmune drug delivery system for
           reprograming the tumor microenvironment and personalized cancer therapy
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Samaresh Sau, Katyayani Tatiparti, Hashem O. Alsaab, Sushil K. Kashaw, Arun K. Iyer
       
  • Extension of quality-by-design concept to the early development phase of
           pharmaceutical R&D processes
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Ildikó Csóka, Edina Pallagi, Tamás L. PaálHere, we propose the extension of the quality-by-design (QbD) concept to also fit the early development phases of pharmaceuticals by adding elements that are currently widely applied, but not yet included in the QbD model in a structured way. These are the introduction of a ‘zero’ preformulation phase (i.e., selection of drug substance, possible dosage forms and administration routes based on the evaluated therapeutic need); building in stakeholders’ (industry, patient, and regulatory) requirements into the quality target product profile (QTTP); and the use of modern quality management tools during the composition and process design phase [collecting critical quality attributes (CQAs) and selection of CPPs) for (still laboratory-scale) design space (DS) development. Moreover, during industrial scale-up, CQAs (as well as critical process parameters; CPPs) can be changed; however, we recommend that the existing QbD elements are reconsidered and updated after this phase.Graphical abstractGraphical abstract for this article
       
  • Strategic R&D transactions in personalized drug development
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Tomohiro Makino, Yeongjoo Lim, Kota KodamaAlthough external collaboration capability influences the development of personalized medicine, key transactions in the pharmaceutical industry have not been addressed. To explore specific trends in interorganizational transactions and key players, we longitudinally surveyed strategic transactions, comparing them with other advanced medical developments, such as antibody therapy, as controls. We found that the financing deals of start-ups have surged over the past decade, accelerating intellectual property (IP) creation. Our correlation and regression analyses identified determinants of financing deals among alliance deals, acquisition deals, patents, research and development (R&D) licenses, market licenses, and scientific papers. They showed that patents positively correlated with transactions, and that the number of R&D licenses significantly predicted financing deals. This indicates, for the first time, that start-ups and investors lead progress in personalized medicine.
       
  • EU decision-making for marketing authorization of advanced therapy
           medicinal products: a case study
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Sofieke de Wilde, Delphi G.M. Coppens, Jarno Hoekman, Marie L. de Bruin, Hubert G.M. Leufkens, Henk-Jan Guchelaar, Pauline MeijA comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.
       
  • ‘Bioexit’: navigating the policy and regulatory pathways for the
           biotechnology industry in a post-Brexit landscape
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Tim K. Mackey, John AnnaloroThe withdrawal of the UK from the European Union (EU) is a complicated event. Although implications vary by industry, the biotechnology sector is especially vulnerable to the consequences of Brexit. Accordingly, here we evaluate potential repercussions under four post-Brexit political pathways: European Economic Area (EEA) affiliation (Norwegian Model); negotiated bilateral access (Swiss Model); limited participation in EU Customs Union (Turkish Model); or independence under the World Trade Organization (WTO) designation. We conclude that all four pathways fail to protect the mutually beneficial UK–EU biotechnology relationship and that alternative pathways need to be explored. Accordingly, we outline a suite of policy mechanisms aimed at ensuring continued EU–UK regulatory synergy, with the central aim of ensuring access to biomedical innovations and ensuring patient safety.
       
  • Accelerating clinical development timelines
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s): Sy Pretorius
       
  • Contents page 2
    • Abstract: Publication date: July 2018Source: Drug Discovery Today, Volume 23, Issue 7Author(s):
       
  • Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic
           purposes
    • Abstract: Publication date: Available online 23 April 2018Source: Drug Discovery TodayAuthor(s): Manish K. Tripathi, Kyle Doxtater, Fatemeh Keramatnia, Chidi Zacheaus, Murali M. Yallapu, Meena Jaggi, Subhash C. ChauhanLong noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.
       
  • The remarkable therapeutic potential of response-based dose
           individualisation in drug trials and patient care
    • Abstract: Publication date: Available online 12 April 2018Source: Drug Discovery TodayAuthor(s): Chao ChenThe FDA reported that most drugs are effective in only 25–62% of patients. Although many drugs require dose individualisation in clinical practice, dose-finding trials usually aim to identify an optimal dose for the patient population. Such a dose would be suboptimal for many patients. Simulations show that individualised dose titration, balancing efficacy against toxicity, can remarkably increase the response rate — doubling it in some situations. Dose titration in a clinical trial can efficiently establish the realistic expectations for the drug’s true utility in a trial setting that reflects clinical practice, as well as generate important knowledge to guide patient care through informative drug labels. This design answers key questions truly relevant to patient care that other designs cannot — will a patient benefit from a given therapy, to what extent and at what dose' Therefore, response-based dose titration should be considered for dose-finding trials, where appropriate, for drugs that will eventually be used this way in the clinic.
       
  • An operational model for GPCR homodimers and its application in the
           analysis of biased signaling
    • Abstract: Publication date: Available online 9 April 2018Source: Drug Discovery TodayAuthor(s): Bin Zhou, Jesús GiraldoG-protein-coupled receptors are one of the most important protein superfamilies as drug targets in drug discovery programs. Their interactions with ligands are influenced by their homomerization. In this study, we propose an operational model for receptor homodimers, which includes constitutive receptor activity. Distinct functional response curves can be obtained from this model, which can satisfactorily depict typical complex experimental data as biphasic and bell-shaped curves. Operational parameters in the model can provide mechanistic explanations for observed functional complexity associated with the cooperativity and intrinsic efficacy of ligands. Because the model presented here is derived from the conceptual framework of operational models, it takes advantage of the body of knowledge coming from the widespread use of this type of modeling. The operational homodimer model can also explain the biased signaling dependent on ligand concentration. In conclusion, this operational homodimer model has a wide range of applications in pharmacological research.
       
  • NTM drug discovery: status, gaps and the way forward
    • Abstract: Publication date: Available online 7 April 2018Source: Drug Discovery TodayAuthor(s): Mu-Lu Wu, Dinah B. Aziz, Véronique Dartois, Thomas DickIncidence of pulmonary diseases caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing at an alarming rate, surpassing tuberculosis in many countries. Current chemotherapies require long treatment times and the clinical outcomes are often disappointing. There is an urgent medical need to discover and develop new, more-efficacious anti-NTM drugs. In this review, we summarize the current status of NTM drug development, and highlight knowledge gaps and scientific obstacles in NTM drug discovery. We propose strategies to reduce biological uncertainties and to begin to populate a NTM drug pipeline with attractive leads and drug candidates.
       
  • The emerging role of copper-64 radiopharmaceuticals as cancer theranostics
    • Abstract: Publication date: Available online 7 April 2018Source: Drug Discovery TodayAuthor(s): Alessandra Boschi, Petra Martini, Emilija Janevik-Ivanovska, Adriano DuattiCopper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly 64Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [64Cu2+] ions. For example, it has been demonstrated that administration of ionic [64Cu2+] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of 64Cu-radiopharmaceuticals in molecular imaging and cancer therapy.
       
  • Update on the main use of biomaterials and techniques associated with
           tissue engineering
    • Abstract: Publication date: Available online 30 March 2018Source: Drug Discovery TodayAuthor(s): Daniela Steffens, Daikelly I. Braghirolli, Natasha Maurmann, Patricia PrankeRegenerative medicine involves the study of cells, signaling cues and biomatrices to restore normal function of tissues and organs. To develop the matrices for use in tissue engineering there are three main groups of biomaterials: (i) naturally derived materials; (ii) synthetic polymers; and (iii) decellularized organ or tissue scaffolds. These biomaterials, in various forms such as hydrogels, nanofibers and 3D scaffolds, among others, have been employed for different tissue regeneration purposes, with several techniques involved in their production, including rapid prototyping, tissue decellularization and electrospinning. In this review, the main topics of hydrogels, 3D printing and electrospun scaffolds, other biomaterials and decellularization and recellularization will be discussed.
       
  • Increased building block access through collaboration
    • Abstract: Publication date: Available online 20 March 2018Source: Drug Discovery TodayAuthor(s): Christopher J. Helal, Alessandra Bartolozzi, Steven D. Goble, Neelakanda S. Mani, Angel Guzman-Perez, Ajay K. Ohri, Zhi-Cai Shi, Chakrapani SubramanyamGraphical abstractGraphical abstract for this article
       
  • N-acylethanolamine hydrolyzing acid amidase inhibition: tools and
           potential therapeutic opportunities
    • Abstract: Publication date: Available online 19 March 2018Source: Drug Discovery TodayAuthor(s): Pauline Bottemanne, Giulio G. Muccioli, Mireille AlhouayekN-acylethanolamines (NAEs) (e.g., N-palmitoylethanolamine, N-arachidonoylethanolamine, N-oleoylethanolamine) are bioactive lipids involved in many physiological processes including pain, inflammation, anxiety, cognition and food intake. Two enzymes are responsible for the hydrolysis of NAEs and therefore regulate their endogenous levels and effects: fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA). As discussed here, extensive biochemical characterization of NAAA was carried out over the years that contributed to a better understanding of NAAA enzymology. An increasing number of studies describe the synthesis and pharmacological characterization of NAAA inhibitors. Recent medicinal chemistry efforts have led to the development of potent and stable inhibitors that enable studying the effects of NAAA inhibition in preclinical disease models, notably in the context of pain and inflammation.
       
  • Corrigendum to “Tocotrienls: the unsaturated sidekick shifting new
           paradigms in vitamin E therapeutics” [Drug Discov. Today 22 (December
           (12)) (2017) 1765–1781]
    • Abstract: Publication date: Available online 7 March 2018Source: Drug Discovery TodayAuthor(s): M.M. Kanchi, M.K. Shanmugam, G. Rane, G. Sethi, A.P. Kumar
       
  • The development of glutamate-based antidepressants is taking longer than
           expected
    • Abstract: Publication date: Available online 1 March 2018Source: Drug Discovery TodayAuthor(s): Ricardo Garay, Carlos A. Zarate, Icilio Cavero, Yong-Ku Kim, Thomas Charpeaud, Phil Skolnick
       
  • Human pharmacological approaches to TRP-ion-channel-based analgesic drug
           development
    • Abstract: Publication date: Available online 30 June 2018Source: Drug Discovery TodayAuthor(s): Iris Weyer-Menkhoff, Jörn LötschThe discovery of novel analgesic drug targets is an active research topic owing to insufficient treatment options for persisting pain. Modulators of temperature-sensing transient receptor potential ion channels (thermoTRPs), in particular TRPV1, TRPV2, TRPM8 and TRPA1, have reached clinical development. This requires access for TRP channels and the effects of specific modulators in humans. This is currently possible via (i) the study of TRP channel function in human-derived cell lines, (ii) immunohistochemical visualization of TRP channel expression in human tissues, (iii) human experimental pain models employing sensitization by means of topical application of TRP channel activators including capsaicin (TRPV1), menthol (TRPM8), mustard oil and cinnamaldehyde (TRPA1), and (iv) the study of phenotypic consequences of human TRP gene variants.
       
  • Mapping genes for drug chronotherapy
    • Abstract: Publication date: Available online 28 June 2018Source: Drug Discovery TodayAuthor(s): Kun Wei, Qian Wang, Jingwen Gan, Shilong Zhang, Meixia Ye, Claudia Gragnoli, Rongling WuGenome-wide association studies have been increasingly used to map and characterize genes that contribute to interindividual variation in drug response. Some studies have integrated the pharmacokinetic (PK) and pharmacodynamic (PD) processes of drug reactions into association mapping, gleaning new insight into how genes determine the dynamic relationship of drug effect and drug dose. Here, we present an evolutionary framework by which two distinct concepts, chronopharmacodynamics and heterochrony (describing variation in the timing and rate of developmental events), are married to comprehend the pharmacogenetic architecture of drug response. The resulting new concept, heterochronopharmacodynamics (HCPD), can better interpret how genes influence drug efficacy and drug toxicity according to the circadian rhythm of the body and changes in drug concentration.
       
  • Delivery systems of local anesthetics in bone surgery: are they efficient
           and safe'
    • Abstract: Publication date: Available online 26 June 2018Source: Drug Discovery TodayAuthor(s): Manon Dupleichs, Qiman Gao, Zahi Badran, Pascal Janvier, Jean-Michel Bouler, Olivier Gauthier, Faleh Tamimi, Elise VerronManagement of postoperative pain following bone surgery includes administration of local anesthetics (LAs). Smart delivery systems, including triggered systems, have been designed to provide a continuous release of LA in situ. However, these systems can provide a high level of LA locally. This review will examine the state-of-the-art regarding the LA delivery systems optimized for management of postoperative pain in bone surgery and will discuss the potential adverse effects of LAs on the overall pathways of bone healing, including the inflammation response phase, hemostasis phase, tissue repair phase and remodeling phase. There is a clinical need to document these effects and the potential impacts on the clinical outcome of the patient.
       
  • Small-molecule inhibitors of macrophage migration inhibitory factor (MIF)
           as an emerging class of therapeutics for immune disorders
    • Abstract: Publication date: Available online 21 June 2018Source: Drug Discovery TodayAuthor(s): Tjie Kok, Anna A. Wasiel, Robbert H. Cool, Barbro N. Melgert, Gerrit J. Poelarends, Frank J. DekkerMacrophage migration inhibitory factor (MIF) is an important cytokine for which an increasing number of functions is being described in the pathogenesis of inflammation and cancer. Nevertheless, the availability of potent and druglike MIF inhibitors that are well-characterized in relevant disease models remains limited. Development of highly potent and selective small-molecule MIF inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we provide an overview of recent advances in the identification of MIF as a pharmacological target in the pathogenesis of inflammatory diseases and cancer. We also give an overview of the current developments in the discovery and design of small-molecule MIF inhibitors and define future aims in this field.
       
  • U-BIOPRED: evaluation of the value of a public–private partnership
           to industry
    • Abstract: Publication date: Available online 21 June 2018Source: Drug Discovery TodayAuthor(s): John H. Riley, Veit J. Erpenbeck, John G. Matthews, Cecile T.J. Holweg, Christopher Compton, Wolfgang Seibold, Timothy Higenbottam, Scott Wagers, Anthony Rowe, David Myles, on behalf of Industry Representatives of the U-BIOPRED Study Group Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-’omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects.
       
  • Renovation as innovation: is repurposing the future of drug discovery
           research'
    • Abstract: Publication date: Available online 21 June 2018Source: Drug Discovery TodayAuthor(s): Arthur Neuberger, Nektarios Oraiopoulos, Donald L. Drakeman
       
  • Neural network and deep-learning algorithms used in QSAR studies: merits
           and drawbacks
    • Abstract: Publication date: Available online 21 June 2018Source: Drug Discovery TodayAuthor(s): Fahimeh Ghasemi, Alireza Mehridehnavi, Alfonso Pérez-Garrido, Horacio Pérez-SánchezThe past two decades are regarded as the golden age of using neural networks (NNs) in chemoinformatics. However, two major issues have arisen concerning their use: redundancy problems when dealing with small data sets, and the large number of compounds with thousands of descriptors, which gives rise to serious overfitting problems. Various NN algorithms, based on feature selection methods and learning algorithms, were devised to avoid these predicaments in drug discovery. Pruning the overfitting problem has emerged as another challenge in recent years, leading to the advent of deep-learning (DL) networks using innovative techniques. Here, we discuss the advantages and disadvantages of the proposed NN algorithms, especially the innovative DL techniques used in ligand-based virtual screening (VS).Graphical abstractGraphical abstract for this article
       
  • The A–Z of Zika drug discovery
    • Abstract: Publication date: Available online 20 June 2018Source: Drug Discovery TodayAuthor(s): Melina Mottin, Joyce V.V.B. Borba, Rodolpho C. Braga, Pedro H.M. Torres, Matheus C. Martini, Jose Luiz Proenca-Modena, Carla C. Judice, Fabio T.M. Costa, Sean Ekins, Alexander L. Perryman, Carolina Horta AndradeDespite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A–Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.
       
  • Importance of target-mediated drug disposition for small molecules
    • Abstract: Publication date: Available online 19 June 2018Source: Drug Discovery TodayAuthor(s): Dennis A. Smith, Robert A.B. van Waterschoot, Neil J. Parrott, Andrés Olivares-Morales, Thierry Lavé, Malcolm RowlandTarget concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development.
       
  • Retinal pigment epithelial cells as a therapeutic tool and target against
           retinopathies
    • Abstract: Publication date: Available online 13 June 2018Source: Drug Discovery TodayAuthor(s): Barbara Pavan, Alessandro DalpiazRetinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood–retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy. Here, we suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells.
       
  • Connecting the pharmacogenetics and personalised medicine community
    • Abstract: Publication date: Available online 13 June 2018Source: Drug Discovery TodayAuthor(s): Christine J. McNamee
       
  • Pragmatic clinical trials: ethical imperatives and opportunities
    • Abstract: Publication date: Available online 12 June 2018Source: Drug Discovery TodayAuthor(s): Shona Kalkman, Ghislaine J.M.W. van Thiel, Diederick E. Grobbee, Johannes J.M. van DeldenPragmatic clinical trials generate robust real-world evidence that holds great potential to better inform decision making regarding new medicines. For clinicians, patients and regulators, this evidence would preferably be available sooner rather than later. This means that, ideally, market authorization of any given medicine is accompanied by evidence obtained from a pragmatic trial. Given the operational and regulatory complexities of pragmatic trials in general, stakeholders tend to be hesitant to employ more pragmatism at the time of market approval. One prominent hurdle for the conduct of pragmatic trials is the concern that pragmatic design features conflict with ethical standards for clinical trials. To encourage timely yet responsible generation of real-world evidence through clinical trials, it is important to delineate exactly which areas, from a societal point of view, demand early pragmatic evaluations. We also urge stakeholders to recognize how the current system of trial ethics oversight already accommodates for more-pragmatic approaches, and how new ideas about their permissibility have progressed in the bioethics literature.
       
  • Drug-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug
           reaction management
    • Abstract: Publication date: Available online 11 June 2018Source: Drug Discovery TodayAuthor(s): Zhining Wen, Yu Liang, Yingyi Hao, Brian Delavan, Ruili Huang, Mike Mikailov, Weida Tong, Menglong Li, Zhichao LiuDrug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information. To elucidate the utility of DIRA, we used precision dosing, concomitant use of DIR drugs, and predictive modeling development to exemplify strategies for idiosyncratic ADR (IADR) management.
       
  • Why are there no drugs indicated for sciatica, the most common chronic
           neuropathic syndrome of all'
    • Abstract: Publication date: Available online 9 June 2018Source: Drug Discovery TodayAuthor(s): John D. Markman, Ralf Baron, Jennifer S. GewandterThis review examines the stark contrast between the successes and failures of the clinical development of analgesics for different types of chronic low back pain (CLBP) syndrome over the past three decades. Multiple drugs with differing mechanisms of action have been developed for nonspecific axial-predominant low back syndromes and yet not a single therapy is indicated for any neuropathic low back pain syndrome (e.g., sciatica). Clinician findings have informed the entry criteria for neuropathic low back pain clinical trials, whereas entry criteria of axial CLBP trials have prioritized only patient reports of pain. This key difference could account for the lack of success in developing therapies for neuropathic low back pain in an era marked by successful development of analgesics for other types of CLBP as well as many chronic pain syndromes associated with nerve injury, such as post-herpetic neuralgia (PHN).
       
  • The fruit fly Drosophila melanogaster as an innovative preclinical ADME
           model for solute carrier membrane transporters, with consequences for
           pharmacology and drug therapy
    • Abstract: Publication date: Available online 8 June 2018Source: Drug Discovery TodayAuthor(s): Yiwen Wang, Bernard Moussian, Elke Schaeffeler, Matthias Schwab, Anne T. NiesSolute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs. Here, we systematically compare current knowledge of SLCs in Drosophila and humans and describe the Drosophila model as an innovative tool for drug development.
       
  • Interrogating the microbiome: experimental and computational
           considerations in support of study reproducibility
    • Abstract: Publication date: Available online 8 June 2018Source: Drug Discovery TodayAuthor(s): Carine Poussin, Nicolas Sierro, Stéphanie Boué, James Battey, Elena Scotti, Vincenzo Belcastro, Manuel C. Peitsch, Nikolai V. Ivanov, Julia HoengThe microbiome is an important factor in human health and disease and is investigated to develop novel therapeutics. Metagenomics leverages advances in sequencing technologies and computational analysis to identify and quantify the microorganisms present in a sample. This field has, however, not yet reached maturity and the international metagenomics community, aware of the current limitations and of the necessity for standardization, has started investigating sources of variability in experimental and computational workflows. The first studies have already resulted in the identification of crucial steps and factors affecting metagenomics data quality, quantification and interpretation. This review summarizes experimental and computational considerations for interrogating the microbiome and establishing reproducible and robust analysis workflows.Graphical abstractGraphical abstract for this article
       
  • Therapeutic application of antibody fragments in autoimmune diseases:
           current state and prospects
    • Abstract: Publication date: Available online 8 June 2018Source: Drug Discovery TodayAuthor(s): João C. FernandesOver the past decades, conventional antibodies have been dissected through different strategies into smaller antigen-binding fragments. Therapeutic solutions built on such fragments can offer several advantages, including the capacity to access challenging epitopes, reduced immunogenicity, lower production costs, and higher stability. Although the development of antibody fragments for cancer therapy has received more attention than any other potential therapeutic application, the development of pharmacological tools based on these molecules for the treatment of autoimmune diseases (AIDs) has been growing at a fast pace. Here, I provide an in-depth characterization of the various formats for the treatment of autoimmune diseases in development across the industry, including antigen-binding fragments (Fab), single-chain variable fragments (scFv), and single variable-domain fragments, as well as multimeric antibody fragments and antibody–drug conjugates.
       
  • Translational strategy: humanized mini-organs
    • Abstract: Publication date: Available online 5 June 2018Source: Drug Discovery TodayAuthor(s): Duong T. Nguyen, Magnus Althage, Maria Chiara Magnone, Sepideh Heydarkhan-HagvallMini-organs engineered from decellularized organs repopulated with human stem cells can transform preclinical model strategies in target validation and biomarker discovery. Recellularized organs are whole humanized organs with preserved native architecture, conformity of the organ, composition of extracellular matrix and vascular matrix structures. With mini-organ models further understanding of developmental biology and assessment of potential therapeutic targets can be elucidated utilizing human induced pluripotent stem cells. As a next step, co-cultured mini-organ models could simulate pharmacokinetics and pharmacodynamics in physiological and pathological conditions. By overcoming key challenges, the development of humanized mini-organs as integrated biotechnology can address the translational gaps between in vitro, ex vivo and in vivo systems for an elevated human target validation model.
       
  • Supermolecular drug challenge to overcome drug resistance in cancer cells
    • Abstract: Publication date: Available online 4 June 2018Source: Drug Discovery TodayAuthor(s): Yasuhiko Onishi, Yuki Eshita, Rui-Cheng Ji, Takashi Kobayashi, Masayasu Onishi, Masaaki Mizuno, Jun Yoshida, Naoji KubotaOvercoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle–cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supermolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation.Graphical abstractGraphical abstract for this article
       
  • Recommendations toward a human pathway-based approach to disease research
    • Abstract: Publication date: Available online 2 June 2018Source: Drug Discovery TodayAuthor(s): Lindsay J. Marshall, Christopher P. Austin, Warren Casey, Suzanne C. Fitzpatrick, Catherine WillettFailures in the current paradigm for drug development have resulted in soaring research and development costs and reduced numbers of new drug approvals. Over 90% of new drug programs fail, the majority terminated at the level of Phase 2/3 clinical trials, largely because of efficacy failures or unexplained toxicity. A recent workshop brought together members from research institutions, regulatory agencies, industry, academia, and nongovernmental organizations to discuss how existing programs could be better applied to understanding human biology and improving drug discovery. Recommendations include increased emphasis on human relevance, better access and curation of data, and improved interdisciplinary and international collaboration.
       
  • Is the adenosine A2B ‘biased’ receptor a valuable target for the
           treatment of pulmonary arterial hypertension'
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Mafalda Bessa-Gonçalves, Bruno Bragança, Eduardo Martins-Dias, Paulo Correia-de-Sá, Ana Patrícia Fontes-SousaPulmonary arterial hypertension (PAH) is a maladaptive disorder characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Adenosine released by injured tissues, such as the lung and heart, influences tissue remodeling through the activation of adenosine receptors. Evidence regarding activation of the low-affinity A2BAR by adenosine points towards pivotal roles of this receptor in processes associated with both acute and chronic lung diseases. Conflicting results exist concerning the beneficial or detrimental roles of the A2B ‘biased’ receptor in right ventricular failure secondary to PAH. In this review, we discuss the pros and cons of manipulating A2BARs as a putative therapeutic target in PAH.
       
  • Cyclodextrins as excipients in tablet formulations
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Jaime Conceição, Oluwatomide Adeoye, Helena Maria Cabral-Marques, José Manuel Sousa LoboThis paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets.
       
  • Can hi-jacking hypoxia inhibit extracellular vesicles in cancer'
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Michelle C. Lowry, Lorraine O’DriscollIncreasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell–cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit.
       
  • Dual-therapy strategy for modification of adiponectin receptor signaling
           in aging-associated chronic diseases
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Masaaki Waragai, Gilbert Ho, Yoshiki Takamatsu, Yuka Shimizu, Hiromu Sugino, Shuei Sugama, Takato Takenouchi, Eliezer Masliah, Makoto HashimotoGiven the paradigm of anti-insulin resistance in therapies for metabolic syndrome, there has been considerable interest in adiponectin (APN), an adipocyte-derived sensitizer of insulin receptor signaling. In contrast to hypoadiponectinemia in metabolic syndrome, evidence suggests that Alzheimer’s disease (AD) and other diseases, including chronic heart failure (CHF) and chronic kidney disease (CKD), are characterized by hyperadiponectinemia as well as the APN/obesity paradoxes, indicating that a decrease in APN might also be beneficial for these diseases. Thus, distinct from metabolic syndrome, it is anticipated that APN receptor antagonists rather than agonists might be effective in therapy for some chronic diseases.
       
  • Quantitative metrics for drug–target ligandability
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Sinisa Vukovic, David J. HugginsLigandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets – some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability.
       
  • Adaptive pathway development for Fabry disease: a clinical approach
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Yvonne Schuller, Maarten Arends, Simon Körver, Mirjam Langeveld, Carla E.M. HollakFabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control.
       
  • The rise of deep learning in drug discovery
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Hongming Chen, Ola Engkvist, Yinhai Wang, Marcus Olivecrona, Thomas BlaschkeOver the past decade, deep learning has achieved remarkable success in various artificial intelligence research areas. Evolved from the previous research on artificial neural networks, this technology has shown superior performance to other machine learning algorithms in areas such as image and voice recognition, natural language processing, among others. The first wave of applications of deep learning in pharmaceutical research has emerged in recent years, and its utility has gone beyond bioactivity predictions and has shown promise in addressing diverse problems in drug discovery. Examples will be discussed covering bioactivity prediction, de novo molecular design, synthesis prediction and biological image analysis.
       
  • Drug targeting of one or more aminoacyl-tRNA synthetase in the malaria
           parasite Plasmodium falciparum
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Yogavel Manickam, Rini Chaturvedi, Palak Babbar, Nipun Malhotra, Vitul Jain, Amit SharmaMalaria remains a major infectious disease and, despite incidence reduction, it threatens resurgence in drug-resistant forms. Antimalarial drugs remain the mainstay of therapeutic options and hence there is a constant need to identify and validate new druggable targets. Plasmodium falciparum aminoacyl-tRNA synthetases (Pf-aaRSs) drive protein translation and are potent targets for development of next-generation antimalarials. Here, we detail advances made in structural-biology-based investigations in Pf-aaRSs and discuss their distribution of druggable pockets. This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria.
       
  • Carbon dots: emerging theranostic nanoarchitectures
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Vijay Mishra, Akshay Patil, Sourav Thakur, Prashant KesharwaniNanotechnology has gained significant interest from biomedical and analytical researchers in recent years. Carbon dots (C-dots), a new member of the carbon nanomaterial family, are spherical, nontoxic, biocompatible, and discrete particles less than 10 nm in diameter. Research interest has focused on C-dots because of their ultra-compact nanosize, favorable biocompatibility, outstanding photoluminescence, superior electron transfer ability, and versatile surface engineering properties. C-dots show significant potential for use in cellular imaging, biosensing, targeted drug delivery, and other biomedical applications. Here we discuss C-dots, in terms of their physicochemical properties, fabrication techniques, toxicity issues, surface engineering and biomedical potential in drug delivery, targeting as well as bioimaging.
       
  • Computational prediction of chemical reactions: current status and outlook
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Ola Engkvist, Per-Ola Norrby, Nidhal Selmi, Yu-hong Lam, Zhengwei Peng, Edward C. Sherer, Willi Amberg, Thomas Erhard, Lynette A. SmythOver the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities.
       
  • Recent progress in the discovery of myeloid differentiation 2 (MD2)
           modulators for inflammatory diseases
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Lingfeng Chen, Weitao Fu, Lulu Zheng, Yi Wang, Guang LiangMyeloid differentiation protein 2 (MD2), together with Toll-like receptor 4 (TLR4), binds lipopolysaccharide (LPS) with high affinity, inducing the formation of the activated homodimer LPS-MD2-TLR4. MD2 directly recognizes the Lipid A domain of LPS, leading to the activation of downstream signaling of cytokine and chemokine production, and initiation of inflammatory and immune responses. However, excessive activation and potent host responses generate severe inflammatory syndromes such as acute sepsis and septic shock. MD2 is increasingly being considered as an attractive pharmacological target for the development of potent anti-inflammatory agents. In this Keynote review, we provide a comprehensive overview of the recent advances in the structure and biology of MD2, and present MD2 modulators as promising agents for anti-inflammatory intervention.
       
  • Redundancy in two major compound databases
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Dimitar Yonchev, Dilyana Dimova, Dagmar Stumpfe, Martin Vogt, Jürgen BajorathPublic repositories of compounds and activity data are of prime importance for pharmaceutical research in academic and industrial settings. Major databases have evolved over the years. Their growth is accompanied by an increasing tendency toward data sharing. This is a positive development but not without potential problems. Using ChEMBL and PubChem as examples, we show that crosstalk between databases also leads to substantial data redundancy that might not be obvious. Redundancy is an important issue because it biases data analysis and knowledge extraction and leads to inflated views of available compounds, assays and activity data. Going forward it will be important to further refine data exchange and deposition criteria and make redundancy as transparent as possible.
       
  • Approved CAR T cell therapies: ice bucket challenges on glaring safety
           risks and long-term impacts
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Ping-Pin Zheng, Johan M. Kros, Jin LiTwo autologous chimeric antigen receptor (CAR) T cell therapies (Kymriah™ and Yescarta™) were recently approved by the FDA. Kymriah™ is for the treatment of pediatric patients and young adults with refractory or relapse (R/R) B cell precursor acute lymphoblastic leukemia and Yescarta™ is for the treatment of adult patients with R/R large B cell lymphoma. In common, both are CD19-specific CAR T cell therapies lysing CD19-positive targets. Their dramatic efficacy in the short term has been highlighted by many media reports. By contrast, their glaring safety gaps behind the miracles remain much less addressed. Here, we focus on addressing the crucial challenges in relation to the gaps.
       
  • Designing an intuitive web application for drug discovery scientists
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Nikiforos Karamanis, Miguel Pignatelli, Denise Carvalho-Silva, Francis Rowland, Jennifer A. Cham, Ian DunhamWe discuss how we designed the Open Targets Platform (www.targetvalidation.org), an intuitive application for bench scientists working in early drug discovery. To meet the needs of our users, we applied lean user experience (UX) design methods: we started engaging with users very early and carried out research, design and evaluation activities within an iterative development process. We also emphasize the collaborative nature of applying lean UX design, which we believe is a foundation for success in this and many other scientific projects.Graphical abstractGraphical abstract for this article
       
  • CROs and CNS research: challenges and trends
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Kemi Olugemo
       
  • Contents page 2
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s):
       
  • Contents page 1
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s):
       
  • Deubiquitinating enzymes in cancer stem cells: functions and targeted
           inhibition for cancer therapy
    • Abstract: Publication date: Available online 1 June 2018Source: Drug Discovery TodayAuthor(s): Kamini Kaushal, Ainsley Mike Antao, Kye-Seong Kim, Suresh RamakrishnaThe ability of cancers to evade conventional treatments, such as chemotherapy and radiation therapy, has been attributed to a subpopulation of cancer stem cells (CSCs). CSCs are regulated by mechanisms similar to those that regulate normal stem cells (NSCs), including processes involving ubiquitination and deubiquitination enzymes (DUBs) that regulate the expression of various factors, such as Notch, Wnt, Sonic Hedgehog (Shh), and Hippo. In this review, we discuss the roles of various DUBs involved in the regulation of core stem cell transcription factors and CSC-related proteins that are implicated in the modulation of cellular processes and carcinogenesis. In addition, we discuss the various DUB inhibitors that have been designed to target processes relevant to cancer and CSC maintenance.
       
  • Why breast cancer signatures are no better than random signatures
           explained
    • Abstract: Publication date: Available online 1 June 2018Source: Drug Discovery TodayAuthor(s): Wilson Wen Bin Goh, Limsoon WongRandom signature superiority (RSS) occurs when random gene signatures outperform published and/or known signatures. Unlike reproducibility and generalizability issues, RSS is relatively underexplored. Yet, understanding it is imperative for better analytical outcome. In breast cancer, RSS correlates strongly with enrichment for proliferation genes and signature size. Removal of proliferation genes from random signatures reduces the predictive power of random signatures. Almost all genes are correlated to a certain extent with the proliferation signature, making complete elimination of its confounding effects impossible. RSS goes beyond breast cancer, because it also exists in other diseases; it is especially strong in other cancers in a platform-independent manner, and less severe, but present nonetheless, in nonproliferative diseases.
       
  • Bioinformatics-based tools in drug discovery: the cartography from single
           gene to integrative biological networks
    • Abstract: Publication date: Available online 1 June 2018Source: Drug Discovery TodayAuthor(s): Pritika Ramharack, Mahmoud E.S. SolimanOriginally developed for the analysis of biological sequences, bioinformatics has advanced into one of the most widely recognized domains in the scientific community. Despite this technological evolution, there is still an urgent need for nontoxic and efficient drugs. The onus now falls on the ‘omics domain to meet this need by implementing bioinformatics techniques that will allow for the introduction of pioneering approaches in the rational drug design process. Here, we categorize an updated list of informatics tools and explore the capabilities of integrative bioinformatics in disease control. We believe that our review will serve as a comprehensive guide toward bioinformatics-oriented disease and drug discovery research.
       
  • The extent and effects of patient involvement in pictogram design for
           written drug information: a short systematic review
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Mara M. van Beusekom, Anne H. Kerkhoven, Mark J.W. Bos, Henk-Jan Guchelaar, Jos M. van den BroekThis short review provides insight into the extent and effectiveness of patient involvement in the design and evaluation of pictograms to support patient drug information. Pubmed, CINAHL, Cochrane Library, Embase, PsycINFO, Academic Search Premier and Web of Science were searched systematically; the 73 included articles were evaluated with the MMAT. We see that, usually, non-patient end-users are involved in the design of pharmaceutical pictograms – patients are more commonly involved in the final evaluation of pictogram success. Repeated involvement of (non-)patients aids the design of effective pharmaceutical pictograms, although there is limited evidence for such effects on patient perception of drug information or health behaviour.
       
  • Bioinspired bone therapies using naringin: applications and advances
    • Abstract: Publication date: June 2018Source: Drug Discovery Today, Volume 23, Issue 6Author(s): Pedro Lavrador, Vitor M. Gaspar, João F. ManoThe use of natural compounds for treating chronic bone diseases holds remarkable potential. Among these therapeutics, naringin, a flavanone glycoside, represents one of the most promising candidates owing to its multifaceted effect on bone tissues. This review provides an up-to-date overview on naringin applications in the treatment of bone disorders, such as osteoporosis and osteoarthritis, and further highlights its potential for stem cell pro-osteogenic differentiation therapies. A critical perspective on naringin clinical translation is also provided. The topic is discussed in light of recently developed biomaterial-based approaches that potentiate its bioavailability and bioactivity. Overall, the reported pro-osteogenic, antiresorptive and antiadipogenic properties establish this flavanone as an exciting candidate for application in bone tissue engineering and regenerative medicine.
       
  • Lipid–polymer hybrid nanocarrier-mediated cancer therapeutics: current
           status and future directions
    • Abstract: Publication date: Available online 29 May 2018Source: Drug Discovery TodayAuthor(s): Neeraj K. Garg, Nikunj Tandel, Rajesh S. Jadon, Rajeev K. Tyagi, Om P. KatareThe new generation of nanoparticles (NPs) encompass attributes of lipids and polymers and are referred to as ‘lipid–polymer hybrid nanoparticles’ (LPHNPs). LPHNPs have helped shed light on the mechanisms involved in targeted and non-specific drug delivery. Research has also highlighted the opportunities and challenges faced by the use of nanomedicine as personalized therapies in oncology. Here, we review the development of LPHNPs as cancer therapeutics, focusing on the methods deployed for enhancing the targeting efficiency and applications of LPHNPs.
       
  • Mesenteric ischemia-reperfusion: an overview of preclinical drug
           strategies
    • Abstract: Publication date: Available online 29 May 2018Source: Drug Discovery TodayAuthor(s): Simona Bertoni, Vigilio Ballabeni, Elisabetta Barocelli, Massimiliano TognoliniMesenteric ischemia is a surgical emergency caused by a transient reduction in blood perfusion to the bowel. Despite accounting for only 0.1% of hospital admissions and 1–2% of gastrointestinal diseases, its elusive symptoms often lead to dramatically high morbidity and mortality rates. The complex cascade of inflammatory events and mediators triggered by mesenteric ischemia-reperfusion (I/R) accounts for the plethora of proposed pharmacological targets and for the current lack of an efficacious drug strategy for its management. It is hoped that a deeper understanding of its pathogenesis and the preclinical therapeutic strategies identified to date and described herein will improve the translation into the clinical setting of the pharmacological armamentarium against a life-threatening disorder that is currently mainly managed surgically.
       
  • Drug metabolism and pharmacokinetic strategies for oligonucleotide- and
           mRNA-based drug development
    • Abstract: Publication date: Available online 28 May 2018Source: Drug Discovery TodayAuthor(s): Shalini Andersson, Madeleine Antonsson, Marie Elebring, Rasmus Jansson-Löfmark, Lars WeidolfOligonucleotide and modified mRNA therapeutics have great potential to treat diseases that are currently challenging to cure and are expanding into global and chronic disease areas such as cancer and various cardiovascular diseases. Advanced drug delivery systems or ligand–drug conjugates are utilized to achieve ‘the right dose to the right target’ to benefit efficacy and safety in patients. Chemistry and ADME characteristics distinguish these therapeutics from small molecules. Understanding the scalability and translatability between species and compound properties is crucial for robust nonclinical PKPD predictions to support clinical study design. Although the field has been developing for three decades, there is still room for innovation but also a need for nonclinical regulatory guidance to address these new modalities.Graphical abstractGraphical abstract for this article
       
  • microRNAs and cardiac stem cells in heart development and disease
    • Abstract: Publication date: Available online 28 May 2018Source: Drug Discovery TodayAuthor(s): Bo Li, Xianmei Meng, Lubo ZhangCumulative evidence has proven that proliferation, differentiation and migration of cardiac stem cells (CSCs) dominate early heart development and contribute to the later occurrence of heart disease. Among other mechanisms, microRNAs work as the ‘fine-tuning’ to modulate the levels of target genes in a specific cell type. The distinct microRNA signatures in CSCs reveal the stages and functions of CSCs. The focus of this review is to summarize recent knowledge advances in CSC proliferation, differentiation and migration and to discuss how microRNAs regulate these processes during heart development and in heart disease. Better understanding of microRNA regulation on CSCs under different situations will enable the unveiling of the mechanisms of heart disease and open new avenues in the therapeutic potentials of microRNA modulation to treat heart disease.
       
  • Is the independence of medical research at stake' On the forces
           shaping the research agenda
    • Abstract: Publication date: Available online 26 May 2018Source: Drug Discovery TodayAuthor(s): Deanna Anderlini
       
  • Understanding drug targets: no such thing as bad news
    • Abstract: Publication date: Available online 24 May 2018Source: Drug Discovery TodayAuthor(s): Ruth A. RobertsHow can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets' Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug. However, the lack of data-rich insight into drug-target safety is one of the major causes of drug-project failure today. Conducting comprehensive target-safety reviews early in the drug discovery process enables project teams to make the right decisions about which drug targets to take forward.
       
  • Reshaping drug development using 3D printing
    • Abstract: Publication date: Available online 24 May 2018Source: Drug Discovery TodayAuthor(s): Atheer Awad, Sarah J. Trenfield, Alvaro Goyanes, Simon Gaisford, Abdul W. BasitThe pharmaceutical industry stands on the brink of a revolution, calling for the recognition and embracement of novel techniques. 3D printing (3DP) is forecast to reshape the way in which drugs are designed, manufactured, and used. Although a clear trend towards personalised fabrication is perceived, here we accentuate the merits and shortcomings of each technology, providing insights into aspects such as the efficiency of production, global supply, and logistics. Contemporary opportunities for 3DP in drug discovery and pharmaceutical development and manufacturing are unveiled, offering a forward-looking view on its potential uses as a digitised tool for personalised dispensing of drugs.
       
  • Progress in the development of nanosensitizers for X-ray-induced
           photodynamic therapy
    • Abstract: Publication date: Available online 24 May 2018Source: Drug Discovery TodayAuthor(s): Xu-Dong Ren, Xiu-Yun Hao, Hong-Cai Li, Mei-Rong Ke, Bi-Yuan Zheng, Jian-Dong HuangIn recent years, photodynamic therapy has been applied in cancer treatment because of its high selectivity and marginal invasion properties. However, the excitation light used has limited ability to penetrate tissue, which creates a stumbling block for its future development. To overcome this, X-rays have been introduced to transmit energy to deeper tissues. Given that a large number of X-ray-induced sensitizers have been designed to facilitate X-ray excitation and generate reactive oxygen species (ROS), this has led to the concept of X-ray-induced photodynamic therapy (X-PDT). After 10 years of development, this treatment now shows good therapeutic effects as well as shortcomings. Going forward, it will be important to improve tumor targeting and a standard deep-seated tumor model should be established.Graphical abstractGraphical abstract for this article
       
  • Bioactive glasses entering the mainstream
    • Abstract: Publication date: Available online 24 May 2018Source: Drug Discovery TodayAuthor(s): Saeid Kargozar, Francesco Baino, Sepideh Hamzehlou, Robert G. Hill, Masoud MozafariOver the past decade, the extended research on bioactive glasses (BGs) has drastically grown because of their bioactive nature and unique ability to deliver therapeutics in tissue engineering, regenerative medicine and even cancer research. These strategies mostly rely on the inherent potential of BGs regarding bonding to the living tissues and accelerating the healing process. All the possibilities are strongly associated with releasing various therapeutic ions from the BG structures into the biological environment. Additionally, some types of glasses [i.e., mesoporous bioactive glasses (MBGs)] can serve as suitable platforms for the delivery of various small molecules and pharmaceutical agents. This class of biomaterials is recognised as a highly versatile delivery system, playing a crucial part in the future of medicine.
       
  • Host-defense peptides and their potential use as biomarkers in human
           diseases
    • Abstract: Publication date: Available online 24 May 2018Source: Drug Discovery TodayAuthor(s): Osmar N. Silva, William F. Porto, Suzana M. Ribeiro, Ingrid Batista, Octavio Luiz FrancoSince the early 19th century, host-defense peptides (HDPs) have been known to play a crucial role in innate host defense. Subsequent work has demonstrated their role in adaptive immunity as well as their involvement in cancer and also a number of inflammatory and/or autoimmune diseases. In addition to these multiple functional activities, several studies have shown that HDP accumulation might be correlated with various human diseases and, therefore, could be used as a biomarkers for such. Thus, research has aimed to validate the clinical use of HDPs for diagnosis, prognosis, and further treatment. In this review, we outline the most recent findings related to the use of HDPs as biomarkers, their clinical and epidemiological value, and the techniques used to determine the levels of HDPs.
       
  • Recent advances in intra-articular drug delivery systems for
           osteoarthritis therapy
    • Abstract: Publication date: Available online 21 May 2018Source: Drug Discovery TodayAuthor(s): Pierre Maudens, Olivier Jordan, Eric AllémannOsteoarthritis (OA) is the most common degenerative disease of the joint. Despite many reports and numerous clinical trials, OA is not entirely understood, and there is no effective treatment available for this disease. To satisfy this unmet medical need, drug delivery systems (DDSs) containing disease-modifying OA drugs (DMOADs) for intra-articular (IA) administration are required to improve the health of OA patients. DDSs should provide controlled and/or sustained drug release, enabling long-term treatment with a reduced number of injections. This paper reviews the role and interaction among different tissues involved in OA and summarizes recent clinical trials and research on DDSs, focusing on small-molecule delivery. To achieve an ideal treatment, various key criteria have been identified to design and develop an IA DDS matching the clinical needs.
       
  • Current approaches to the discovery of novel inhaled medicines
    • Abstract: Publication date: Available online 20 May 2018Source: Drug Discovery TodayAuthor(s): Peter Strong, Kazuhiro Ito, John Murray, Garth RapeportInhaled administration is underutilised because the drug discovery process is viewed as challenging, risky, and expensive. However, unmet medical need continues to grow, and significant opportunities exist to discover novel inhaled medicines delivering the required lung concentrations while minimising systemic exposure. This profile could be achieved by a combination of properties, including lung retention and low oral bioavailability. Property-based rules exist for orally administered compounds, but there has been limited progress defining in silico predictors to guide the discovery of novel inhaled drugs. Recently, the use of informative cell- and tissue-based screens has greatly facilitated the identification of compounds with optimal characteristics for inhaled delivery. Here, we address opportunities for novel inhaled drugs, and the key challenges and uncertainties hampering progress.
       
  • Nanogels as potential drug nanocarriers for CNS drug delivery
    • Abstract: Publication date: Available online 20 May 2018Source: Drug Discovery TodayAuthor(s): Arti Vashist, Ajeet Kaushik, Atul Vashist, Jyoti Bala, Roozbeh Nikkhah-Moshaie, Vidya Sagar, Madhavan NairHydrogel-based drug delivery systems (DDSs) have versatile applications such, as tissue engineering, scaffolds, drug delivery, and regenerative medicines. The drawback of higher size and poor stability in such DDSs are being addressed by developing nano-sized hydrogel particles, known as nanogels, to achieve the desired biocompatibility and encapsulation efficiency for better efficacy than conventional bulk hydrogels. In this review, we describe advances in the development of nanogels and their promotion as nanocarriers to deliver therapeutic agents to the central nervous system (CNS). We also discuss the challenges, possible solutions, and future prospects for the use of nanogel-based DDSs for CNS therapies.
       
  • Structural basis for selective inhibition of antibacterial target MraY, a
           membrane-bound enzyme involved in peptidoglycan synthesis
    • Abstract: Publication date: Available online 18 May 2018Source: Drug Discovery TodayAuthor(s): Jenny Hering, Elin Dunevall, Margareta Ek, Gisela BrändénThe rapid growth of antibiotic-resistant bacterial infections is of major concern for human health. Therefore, it is of great importance to characterize novel targets for the development of antibacterial drugs. One promising protein target is MraY (UDP-N-acetylmuramyl-pentapeptide: undecaprenyl phosphate N-acetylmuramyl-pentapeptide-1-phosphate transferase or MurNAc-1-P-transferase), which is essential for bacterial cell wall synthesis. Here, we summarize recent breakthroughs in structural studies of bacterial MraYs and the closely related human GPT (UDP-N-acetylglucosamine: dolichyl phosphate N-acetylglucosamine-1-phosphate transferase or GlcNAc-1-P-transferase). We present a detailed comparison of interaction modes with the natural product inhibitors tunicamycin and muraymycin D2. Finally, we speculate on possible routes to design an antibacterial agent in the form of a potent and selective inhibitor against MraY.
       
  • Renal Pre-Competitive Consortium (RPC2): discovering
           therapeutic targets together
    • Abstract: Publication date: Available online 18 May 2018Source: Drug Discovery TodayAuthor(s): Mark Tomilo, Heather Ascani, Barbara Mirel, Maria Chiara Magnone, Carol Moreno Quinn, Anil Karihaloo, Kevin Duffin, Uptal D. Patel, Matthias KretzlerDespite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic–industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry. The Renal Pre-Competitive Consortium (RPC2) aims to accelerate novel drug development for kidney diseases through a systems biology approach. Here, we describe the rationale, philosophy, establishment, and initial results of this strategy.
       
  • Bioorthogonal chemistry in bioluminescence imaging
    • Abstract: Publication date: Available online 18 May 2018Source: Drug Discovery TodayAuthor(s): Aurélien Godinat, Arkadiy A. Bazhin, Elena A. GounBioorthogonal chemistry has developed significant over the past few decades, to the particular benefit of molecular imaging. Bioluminescence imaging (BLI) along with other imaging modalities have significantly benefitted from this chemistry. Here, we review bioorthogonal reactions that have been used to signific antly broaden the application range of BLI.
       
  • Corticosteroids and perinatal hypoxic-ischemic brain injury
    • Abstract: Publication date: Available online 17 May 2018Source: Drug Discovery TodayAuthor(s): Katherine R. Concepcion, Lubo ZhangPerinatal hypoxic-ischemic (HI) brain injury is the major cause of neonatal mortality and severe long-term neurological morbidity. Yet, the effective therapeutic interventions currently available are extremely limited. Corticosteroids act on both mineralocorticoid (MR) and glucocorticoid (GR) receptors and modulate inflammation and apoptosis in the brain. Neuroinflammatory response to acute cerebral HI is a major contributor to the pathophysiology of perinatal brain injury. Here, we give an overview of current knowledge of corticosteroid-mediated modulations of inflammation and apoptosis in the neonatal brain, focusing on key regulatory cells of the innate and adaptive immune response. In addition, we provide new insights into targets of MR and GR in potential therapeutic strategies that could be beneficial for the treatment of infants with HI brain injury.
       
  • Targeting HIF-2α as therapy for advanced cancers
    • Abstract: Publication date: Available online 16 May 2018Source: Drug Discovery TodayAuthor(s): Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar JegatheesanHypoxia-inducible factors (HIF-1α, -2α -3α, and -β) are key factors that control hypoxia-induced carcinogenic pathways. HIF-1α is predominantly involved in the early stages of cancer, whereas HIF-2α is actively involved in the later stages; in addition, chronic (prolonged) rather than acute (short) hypoxia is a feature of metastasis and chemoresistance that occur during the later stages of cancer. Oncometabolites, onco-miRNAs, glucose deprivation, pseudohypoxia, cytokine/chemokine secretion, and some unique upstream proteins are involved in the signaling switch from HIF-1α to HIF-2α; thus, understanding this signaling switch is critical for the treatment of advanced cancer. In this review, we highlight data relating to HIF-2α rather than HIF-1α signaling in cancer pathways and discuss prospective drugs that target this important factor.
       
  • Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced
           cellular metabolism in cancer cells
    • Abstract: Publication date: Available online 14 May 2018Source: Drug Discovery TodayAuthor(s): Lakhveer Singh, Sara Aldosary, Abdulaziz S. Saeedan, Mohd. Nazam Ansari, Gaurav KaithwasHypoxia-inducible factor-1α (HIF-1α) shifts the metabolism of glucose from highly efficient oxidative phosphorylation to less efficient glycolysis. Pyruvic acid thus accumulated is oxidized to lactic acid which is pumped out in the tumor microenvironment. Protons generated from the pentose phosphate pathway (PPP) and upon hydrolysis of ATP further enhance the acidity in the tumor microenvironment. The resultant pH in the tumor microenvironment activates an endoplasmic reticulum protein: sterol regulatory element binding protein-1c (SREBP-1c), which once activated enhances proliferation of the tumor cell. Prolyl hydroxylase 2 (PHD2) is a negative regulator of HIF-1α and causes degradation of HIF-1α in the presence of oxygen. Chemical activation of PHD2 can downregulate HIF-1α and thus restore all its effects. The present review is an attempt to describe PHD2 as the target to combat cancer hypoxia and consequential cellular and metabolic alterations.
       
  • Translation of innovative chemistry into screening libraries: an exemplar
           partnership from the European Lead Factory
    • Abstract: Publication date: Available online 9 May 2018Source: Drug Discovery TodayAuthor(s): Remy Morgentin, Mark Dow, Anthony Aimon, George Karageorgis, Tuomo Kalliokoski, Didier Roche, Stephen Marsden, Adam NelsonThe identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21 119 distinctive screening compounds to the ELF Joint European Compound Library. The partnership could serve as a blueprint for the translation of innovative academic chemistry into discovery programmes.
       
  • Machine learning in chemoinformatics and drug discovery
    • Abstract: Publication date: Available online 8 May 2018Source: Drug Discovery TodayAuthor(s): Yu-Chen Lo, Stefano E. Rensi, Wen Torng, Russ B. AltmanChemoinformatics is an established discipline focusing on extracting, processing and extrapolating meaningful data from chemical structures. With the rapid explosion of chemical ‘big’ data from HTS and combinatorial synthesis, machine learning has become an indispensable tool for drug designers to mine chemical information from large compound databases to design drugs with important biological properties. To process the chemical data, we first reviewed multiple processing layers in the chemoinformatics pipeline followed by the introduction of commonly used machine learning models in drug discovery and QSAR analysis. Here, we present basic principles and recent case studies to demonstrate the utility of machine learning techniques in chemoinformatics analyses; and we discuss limitations and future directions to guide further development in this evolving field.
       
  • Targeting cancer metabolism to develop human lactate dehydrogenase
           (hLDH)5 inhibitors
    • Abstract: Publication date: Available online 8 May 2018Source: Drug Discovery TodayAuthor(s): Shao-Lin Zhang, Yun He, Kin Yip TamCancer cells feature a switch in glucose metabolism from oxidative phosphorylation to cytoplasm-based glycolysis. This altered cellular metabolic pathway meets the survival and proliferation needs for tumor progression. Targeting the metabolic remodeling could offer opportunities for developing effective anticancer therapeutics. Human lactate dehydrogenase (hLDH)5 plays a crucial part in the promotion of glycolysis and is overexpressed in various human tumors, and thus could be a potential anticancer drug target. Here, we briefly discuss the roles of hLDH5 and its connections with cancer metabolism. Then, we review the reported small molecules in light of their binding modes to hLDH5. Finally, possible directions for future development of hLDH5 inhibitors are proposed. We hope that this review will provoke interest in developing hLDH5 inhibitors.Graphical abstractGraphical abstract for this article
       
  • Real-world evidence approach to traditional herbal medicinal products
    • Abstract: Publication date: Available online 7 May 2018Source: Drug Discovery TodayAuthor(s): Xinyu WengThere are tens of thousands of traditional herbal medicinal products (THMPs) on the market worldwide but few of them have gone through tests for efficacy and safety in randomized controlled trials (RCTs). THMP regulation is a global challenge. Many countries are faced with this dilemma: a looser regulation could present a significant risk to the public, whereas a tougher regulation might limit the availability of THMPs to the public. In the past two decades, the USA, the European Union (EU), China and other countries have enacted different provisions for THMPs. Different regulatory approaches reflect different cultures, ideology and experience in the regulation of THMPs, and none of them lacks controversy.
       
  • When fragments link: a bibliometric perspective on the development of
           fragment-based drug discovery
    • Abstract: Publication date: Available online 5 May 2018Source: Drug Discovery TodayAuthor(s): Angelo K.S. Romasanta, Peter van der Sijde, Iina Hellsten, Roderick E. Hubbard, Gyorgy M. Keseru, Jacqueline van Muijlwijk-Koezen, Iwan J.P. de EschFragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university–industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields.
       
  • Protein–peptide docking: opportunities and challenges
    • Abstract: Publication date: Available online 4 May 2018Source: Drug Discovery TodayAuthor(s): Maciej Ciemny, Mateusz Kurcinski, Karol Kamel, Andrzej Kolinski, Nawsad Alam, Ora Schueler-Furman, Sebastian KmiecikPeptides have recently attracted much attention as promising drug candidates. Rational design of peptide-derived therapeutics usually requires structural characterization of the underlying protein–peptide interaction. Given that experimental characterization can be difficult, reliable computational tools are needed. In recent years, a variety of approaches have been developed for ‘protein–peptide docking’, that is, predicting the structure of the protein–peptide complex, starting from the protein structure and the peptide sequence, including variable degrees of information about the peptide binding site and/or conformation. In this review, we provide an overview of protein–peptide docking methods and outline their capabilities, limitations, and applications in structure-based drug design. Key challenges are also briefly discussed, such as modeling of large-scale conformational changes upon binding, scoring of predicted models, and optimal inclusion of varied types of experimental data and theoretical predictions into an integrative modeling process.
       
  • Cochlear hair cell regeneration: an emerging opportunity to cure
           noise-induced sensorineural hearing loss
    • Abstract: Publication date: Available online 4 May 2018Source: Drug Discovery TodayAuthor(s): Ibrahima Youm, Wei LiIn mammals, cochlear hair cells have a pivotal role in transducing mechanical energy into electrical signals. Cochlear hair cells are sensitive to acoustic trauma, drug insults, aging, and environmental or genetic influences that can cause permanent hearing loss. Currently, many researchers have focused on noise-induced sensorineural hearing loss (SNHL). Noise-induced SNHL is primarily caused by damage to hair cells of the cochlear sensory epithelium. Here, we summarize recent progress in restoring the sensory epithelium after SNHL resulting from noise exposure. The prevalent strategy to regenerate cochlear hair cells is through transdifferentiation of the supporting cells via the inhibition of the NOTCH 1 pathway.
       
 
 
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