Cover Story February 2017 Volume 22 Number 2 pp. 195–476 Cover Story The lead story in this issue of Drug Discovery Today is by Eugenia Gentile and Grazia M Liuzzi of the Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Italy and is entitled: “Marine pharmacology: therapeutic targeting of matrix metalloproteinases... CONTENTS EDITORIAL 195 Are SAR tables obsolete? Celerino Abad-Zapatero FEATURE 199 The SULSA Assay Development Fund: accelerating translation of newbiology from academia to pharma Stuart P. McElroy, Philip S. Jones and Denise V. Barrault 204 Semiconductor technology in protein kinase research and drug discovery:sensing a revolution Nikhil Bhalla, Mirella Di Lorenzo,... Page 5 DRUG DISCOVERY TODAY Editorial Editor: Steve Carney Content Development Managers: Pien Spijker and Jasmin Bakker Journal Manager: Rohini Nair Publisher: Jaap van Harten Editorial Enquiries: Drug Discovery Today Elsevier 32 Jamestown Road, London, NW1 7BY, UK Tel: +44 (0)20 7424 4200 Fax: +44 (0)1865 853067 Email: ddt@drugdiscoverytoday.com ADVISORY EDITORIAL BOARD Jurgen Bajorath University of Bonn, Germany Walter Blackstock Experimental Therapeutics Centre, Singapore David Brayden University College Dublin, Ireland Paul Caron Integrated Profi ling, USA David Cavalla Numedicus Ltd., UK David Clark Argenta Discovery, UK Dalia Cohen ALN Associates, USA Donald Daley Argenta Discovery, UK Sean Ekins Collaborations in Chemistry, USA... FORTHCOMING ARTICLES: Special issue on Tuberculosis Raising awareness of the importance of funding for tuberculosis small-molecule research. By Giovanna Riccardi, Iain G. Old and Sean Ekins. A new ‘golden age’ for the antitubercular target InhA. By Kaja Rožman, Izidor Sosic, Raquel Fernandez, Robert Young, Alfonso Mendoza, Stanislav Gobec and Lourdes Encinas. Identifi... Editorial Page 7 Are SAR tables obsolete? Perhaps it is because I am not a professional medicinal chemist, or possibly it is because I am a person that prefers the visual presentation of data as opposed to a long list of numbers in parallel vertical columns; either way, the fact is that the conventional structure–activity relation tables... Perspective Page 11 The SULSA Assay Development Fund: accelerating translation of new biology from academia to pharma With industry increasingly sourcing preclinical drug discovery projects from academia it is important that new academic discoveries are enabled through translation with HTS-ready assays. However, many scientifically interesting, novel molecular targets lack associated high-quality, robust assays suitable for hit finding and development. To bridge this gap, the Scottish Universities Life... Page 16 Semiconductor technology in protein kinase research and drug discovery: sensing a revolution Since the discovery of protein kinase activity in 1954, close to 600 kinases have been discovered that have crucial roles in cell physiology. In several pathological conditions, aberrant protein kinase activity leads to abnormal cell and tissue physiology. Therefore, protein kinase inhibitors are investigated as potential treatments for several diseases,... Reviews Page 22 Design of efficient computational workflows for in silico drug repurposing Here, we provide a comprehensive overview of the current status of in silico repurposing methods by establishing links between current technological trends, data availability and characteristics of the algorithms used in these methods. Using the case of the computational repurposing of fasudil as an alternative autophagy enhancer, we suggest a... Page 35 Amyloid beta modulators and neuroprotection in Alzheimer’s disease: a critical appraisal Multiple cellular changes have been identified as being involved in Alzheimer’s disease (AD) pathogenesis, including mitochondrial damage, synaptic loss, amyloid beta (Ab) production and/or accumulation, inflammatory responses, and phosphorylated tau formation and/or accumulation. Studies have established that Ab-induced synaptic dysfunction is dependent on abnormal amyloid precursor protein (APP) processing caused... Page 46 The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts Anti-infective drugs have had a key role in the contemporary world, contributing to dramatically decrease mortality rates caused by infectious diseases worldwide. Antimicrobial peptides (AMPs) are multifunctional effectors of the innate immune system of mucosal surfaces and present antimicrobial activity against a range of pathogenic viruses, bacteria, and fungi. However,... Page 61 Molecular dynamics-driven drug discovery: leaping forward with confidence Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities... Page 82 Doxorubicin: nanotechnological overviews from bench to bedside Doxorubicin (DOX) is considered one of the most effective chemotherapeutic agents, used as a first-line drug in numerous types of cancer. Nevertheless, it exhibits serious adverse effects, such as lethal cardiotoxicity and dose-limiting myelosuppression. In this review, we focus on the description and the clinical benefits of different DOX-loaded nanotechnological... Page 94 Downregulation of melanogenesis: drug discovery and therapeutic options Melanin, primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a process called melanogenesis. However, the abnormal accumulation of melanin causes dermatological problems such as cafe-au-lait macules ephelides (freckles), solar lentigo (age spots) and melasma, as well as cancer and vitiligo. Hence the regulation... Page 111 Marine pharmacology: therapeutic targeting of matrix metalloproteinases in neuroinflammation Alterations in matrix metalloproteinase (MMP) expression and activity are recognized as key pathogenetic events in several neurological disorders. This evidence makes MMPs possible therapeutic targets. The search for substances that can inhibit MMPs is moving progressively toward the screening of natural products. In particular, marine bioprospecting could be promising for... Page 126 Dendrimer nanoarchitectures for cancer diagnosis and anticancer drug delivery Dendrimers are novel nanoarchitectures with unique properties including a globular 3D shape, a monodispersed unimicellar nature and a nanometric size range. The availability of multiple peripheral functional groups and tunable surface engineering enable the facile modification of the dendrimer surface with different therapeutic drugs, diagnostic agents and targeting ligands. Drug... Page 139 Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations Page 152 Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters Currently, because globalization, the pharmaceutical industry is facing enormous challenges to comply with regulatory matters. Reduced patent life and overall decreased profitability of newly discovered drugs are also forcing the pharmaceutical industry to shorten the drug development time with maximum throughput. Therefore, continuous manufacturing (CM) processes via hot melt extrusion... Page 164 Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid... Page 178 Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately... Page 189 Molecular similarity considerations in the licensing of orphan drugs The large costs associated with modern drug discovery mean that governments and regulatory bodies need to provide economic incentives to promote the development of orphan drugs (i.e., medicinal products that are designed to treat rare disease that affect only small numbers of patients). Under European Union (EU) legislation, a medicine... Page 194 Bioimaging of nanoparticles: the crucial role of discriminating nanoparticles from free probes The biological fate of nanocarriers has yet to be fully explored, mainly because of the lack of functional tools like probes to identify integral nanocarriers in the body. Understanding their in vivo fate remains as the bottleneck to the development of nanomedicines. Bioimaging results based on conventional fluorescent or radioactive... Page 200 New concepts in asthma: clinical phenotypes and pathophysiological mechanisms Asthma is among the most common chronic inflammatory diseases worldwide. Recent evidence indicates that the pathogenesis shows a high degree of heterogeneity. Patient subsets have been identified that exhibit different cellular and molecular patterns of dysregulation. A prominent example is eosinophilic Th2-driven asthma. These unique and molecular patterns are termed... Page 209 Organs-on-chips: research and commercial perspectives Traditional preclinical drug testing methods utilize animal models to predict pharmacology and toxicology profiles. However, the data obtained from such methods cannot be directly extrapolated to humans and often do not provide a safe starting dose for first-in-human studies. To overcome these limitations, researchers have developed organs-on-chips – microfluidic devices... Page 216 Global vision of druggability issues: applications and perspectives During the preliminary stage of a drug discovery project, the lack of druggability information and poor target selection are the main causes of frequent failures. Elaborating on accurate computational druggability prediction methods is a requirement for prioritizing target selection, designing new drugs and avoiding side effects. In this review, we... Page 228 Protein delivery to the back of the eye: barriers, carriers and stability of anti-VEGF proteins Utilization of the full clinical potential of many novel therapeutic proteins designed for diseases affecting the posterior segment of the eye has often been limited because of their inherent instability and the difficulty in overcoming various ocular barriers. Intravitreal injection is currently the only approved mode of administration, although it... Page 236 miRNA nanotherapeutics for cancer MicroRNAs (miRNAs) are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to... Page 245 Fragmentation in the biopharmaceutical industry The large number of biopharmaceutical mergers and acquisitions (MA) that occurred over the past decade has generated questions about whether the industry is consolidating around too-few players, negatively impacting both the number of medicines developed and overall innovation. However, closer examination of the level of biopharmaceutical consolidation by prescription sales... Page 252 Mimicking the ocular environment for the study of inflammatory posterior eye disorders The common inflammatory posterior eye disorders, age-related degeneration and glaucoma often lead to irreversible vision loss. Current treatments do not target early stages or prevent disease progression. Consequently, the identification of biomarkers or early disease models that can accurately mimic the pathological processes involved is essential. Although none of the... Page 259 Designed covalent allosteric modulators: an emerging paradigm in drug discovery Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable tool in drug discovery. Here, we review... Page 266 Peptidomimetic therapeutics: scientific approaches and opportunities Natural endogenously occurring peptides exhibit desirable medicinal properties, but are often limited in application by rapid proteolysis and inadequate membrane permeability. However, editing naturally occurring peptide sequences to develop peptidomimetic analogs created a promising class of therapeutics that can augment or inhibit molecular interactions. Here, we discuss a variety of... Page 275 UPLC–MS for metabolomics: a giant step forward in support of pharmaceutical research Metabolomics is a relatively new and rapidly growing area of post-genomic biological research. As use of metabolomics technology grows throughout the spectrum of drug discovery and development, and its applications broaden, its impact is expanding dramatically. This review seeks to provide the reader with a brief history of the development... Page 283 The unique status of first-in-human studies: strengthening the social value requirement For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they... Diary Page 288 diary Each month we publish brief details of forthcoming meetings. The diary is updated regularly. If you are organizing a future meeting, please help us to maintain an effi cient service by sending the appropriate details to the Editor well in advance. Entries new to this issue are marked with an... 更多信息请浏览： DDT_2017_02（195-298）.pdf DDT_2017_02（299-396）.pdf DDT_2017_02（397-476）.pdf If you do not wish to receive further emails relating to Drug Discovery Today , please click here to unsubscribe: www.drugdiscoverytoday.com
TABLE OF CONTENTS Volume 87, Issue 1 (January 2010) In this issue In This Issue Editorial News Views Perspectives State of the Art Research Discovery Development Regulation Use Also new AOP Sign up for e-alerts Recommend to your library Web feed Subscribe Advertisement Clinical Pharmacology Therapeutics ( CPT ) continues to drive advances in the nature, efficacy, and evaluation of clinical pharmacology and therapeutics. Themed issues for the year provide a range of hot topics. Hot issues in 2010 include: Nutraceuticals, Drug Discovery Development; Precompetitive Collaboration More themes covered. Important issues addressed. Crucial research from the field. Ensure your access If you are unable to access the articles in this Table of Contents e-alert, your library may not subscribe to this journal. Our online recommendation form is a simple way to make your librarian aware that this journal is valuable to your research. Recommend this journal to your librarian now ! In This Issue Top IN THIS ISSUE Clin Pharmacol Ther 2010 87: 1; 10.1038/clpt.2009.256 Abstract | Full Text Editorial Top EDITORIAL Drug Transporters: Recent Advances and Therapeutic Applications R MFranke and ASparreboom Clin Pharmacol Ther 2010 87: 3-7; 10.1038/clpt.2009.239 Abstract | Full Text News Views Top HIGHLIGHTS Clin Pharmacol Ther 2010 87: 8-9; 10.1038/clpt.2009.257 Abstract | Full Text ASCPT NEWS Clin Pharmacol Ther 2010 87: 10-12; 10.1038/clpt.2009.238 Abstract | Full Text Perspectives Top POINT/COUNTERPOINT Transporters in Drug-Refractory Epilepsy: Clinical Significance NMarchi, JGonzalez-Martinez, M-TNguyen, TGranata and DJanigro Clin Pharmacol Ther 2010 87: 13-15; 10.1038/clpt.2009.225 Abstract | Full Text ABC Transporters in Drug-Refractory Epilepsy: Limited Clinical Significance of Pharmacogenetics? ICascorbi Clin Pharmacol Ther 2010 87: 15-18; 10.1038/clpt.2009.237 Abstract | Full Text COMMENTARIES A Piece in the Puzzle of Personalized Medicine H KKroemer, H EMeyer and zuSchwabedissen Clin Pharmacol Ther 2010 87: 19-20; 10.1038/clpt.2009.219 Abstract | Full Text Biomarker Qualification via PublicPrivate Partnerships S LEck and S MPaul Clin Pharmacol Ther 2010 87: 21-23; 10.1038/clpt.2009.193 Abstract | Full Text Quantification of T-Cell Proliferation for Individualizing Immunosuppressive Therapy for Transplantation Patients HOhdan Clin Pharmacol Ther 2010 87: 23-26; 10.1038/clpt.2009.171 Abstract | Full Text CONFERENCE PROCEEDINGS Expediting Patients Access to Medicines by Improving the Predictability of Drug Development and the Regulatory Approval Process LLiberti, ABreckenridge, H GEichler, RPeterson, NMcAuslane and SWalker Clin Pharmacol Ther 2010 87: 27-31; 10.1038/clpt.2009.179 Abstract | Full Text The International Transporter Consortium: A Collaborative Group of Scientists From Academia, Industry, and the FDA S-MHuang, LZhang and K MGiacomini Clin Pharmacol Ther 2010 87: 32-36; 10.1038/clpt.2009.236 Abstract | Full Text LETTERS TO THE EDITOR Rupatadine and Heart Rhythm Disturbances RFit and JBorja Clin Pharmacol Ther 2010 87: 37; advance online publication, September 2, 2009; 10.1038/clpt.2009.118 Abstract | Full Text Response to Rupatadine and Heart Rhythm Disturbances ACarvajal, DMacas, ISalado, MSinz, SOrtega, CCampo, JGarca del Pozo, L HMartn Arias, AVelasco, SGonalves, RPombal and RCarmona Clin Pharmacol Ther 2010 87: 37-38; advance online publication, September 2, 2009; 10.1038/clpt.2009.157 Abstract | Full Text State of the Art Top STATE OF THE ART Drug Uptake Systems in Liver and Kidney: A Historic Perspective BHagenbuch Clin Pharmacol Ther 2010 87: 39-47; advance online publication, November 18, 2009; 10.1038/clpt.2009.235 Abstract | Full Text Research Top REPORT Comparison of Critical DrugDrug Interaction Listings: The Department of Veterans Affairs Medical System and Standard Reference Compendia E LOlvey, SClauschee and D CMalone Clin Pharmacol Ther 2010 87: 48-51; advance online publication, November 4, 2009; 10.1038/clpt.2009.198 Abstract | Full Text ARTICLES Loss-of-Function CYP2C9 Variants Improve Therapeutic Response to Sulfonylureas in Type 2 Diabetes: A Go-DARTS Study KZhou, LDonnelly, LBurch, RTavendale, A S FDoney, GLeese, A THattersley, M IMcCarthy, A DMorris, C CLang, C N APalmer and E RPearson Clin Pharmacol Ther 2010 87: 52-56; advance online publication, September 30, 2009; 10.1038/clpt.2009.176 Abstract | Full Text Genetic Factors ( VKORC1, CYP2C9, EPHX1, and CYP4F2 ) Are Predictor Variables for Warfarin Response in Very Elderly, Frail Inpatients EPautas, CMoreau, IGouin-Thibault, J-LGolmard, IMah, CLegendre, ETaillandier-Hriche, BDurand-Gasselin, A-MHoullier, PVerrier, PBeaune, M-ALoriot and VSiguret Clin Pharmacol Ther 2010 87: 57-64; advance online publication, September 30, 2009; 10.1038/clpt.2009.178 Abstract | Full Text UDP-Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo SRiedmaier, KKlein, UHofmann, J EKeskitalo, P JNeuvonen, MSchwab, MNiemi and U MZanger Clin Pharmacol Ther 2010 87: 65-73; advance online publication, September 30, 2009; 10.1038/clpt.2009.181 Abstract | Full Text A Pharmacovigilance Program From Laboratory Signals for the Detection and Reporting of Serious Adverse Drug Reactions in Hospitalized Patients ERamirez, A JCarcas, A MBorobia, S HLei, EPiana, SFudio and JFrias Clin Pharmacol Ther 2010 87: 74-86; advance online publication, November 4, 2009; 10.1038/clpt.2009.185 Abstract | Full Text Ocular Hemodynamic Effects of Nitrovasodilators in Healthy Subjects DSchmidl, EPolska, BKiss, SSacu, GGarhofer and LSchmetterer Clin Pharmacol Ther 2010 87: 87-92; advance online publication, November 4, 2009; 10.1038/clpt.2009.186 Abstract | Full Text Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants D KBenjamin, Jr, P BSmith, AArrieta, LCastro, P JSnchez, DKaufman, L JArnold, L LKovanda, TSawamoto, D NBuell, W WHope and T JWalsh Clin Pharmacol Ther 2010 87: 93-99; advance online publication, November 4, 2009; 10.1038/clpt.2009.200 Abstract | Full Text The Role of Organic AnionTransporting Polypeptides and Their Common Genetic Variants in Mycophenolic Acid Pharmacokinetics NPicard, S WYee, J-BWoillard, YLebranchu, YLe Meur, K MGiacomini and PMarquet Clin Pharmacol Ther 2010 87: 100-108; advance online publication, November 4, 2009; 10.1038/clpt.2009.205 Abstract | Full Text Discovery Development Top DISCOVERY The Pharmacogenomics of Membrane Transporters Project: Research at the Interface of Genomics and Transporter Pharmacology D LKroetz, S WYee and K MGiacomini Clin Pharmacol Ther 2010 87: 109-116; advance online publication, November 25, 2009; 10.1038/clpt.2009.226 Abstract | Full Text TRANSLATIONAL MEDICINE Transporters as Drug Targets: Discovery and Development of NPC1L1 Inhibitors J LBetters and LYu Clin Pharmacol Ther 2010 87: 117-121; advance online publication, November 11, 2009; 10.1038/clpt.2009.209 Abstract | Full Text DEVELOPMENT Transporters for Drug Delivery and as Drug Targets in Parasitic Protozoa S MLandfear Clin Pharmacol Ther 2010 87: 122-125; advance online publication, July 1, 2009; 10.1038/clpt.2009.116 Abstract | Full Text Regulation Use Top PRACTICE Intravenous-to-Oral Switch in Anticancer Chemotherapy: A Focus on Docetaxel and Paclitaxel S L WKoolen, J HBeijnen and J H MSchellens Clin Pharmacol Ther 2010 87: 126-129; advance online publication, November 18, 2009; 10.1038/clpt.2009.233 Abstract | Full Text Transporter Pharmacogenetics and Statin Toxicity MNiemi Clin Pharmacol Ther 2010 87: 130-133; advance online publication, November 4, 2009; 10.1038/clpt.2009.197 Abstract | Full Text Advertisement Clinical Pharmacology Therapeutics - now accepting papers! 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