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Drug Discovery Today

Archana Vimal, Awanish Kumar
Allosterism has emerged as an innovative and significant mode of drug discovery. It facilitates the targeting of an allosteric site that is unique and more specific. A relatively new approach to allosteric regulation is the morpheein model, a concerted dissociative model that describes the equilibrium of alternate quaternary structure assemblies, whose architectures are dictated by alternate conformations in the dissociated state. It is involved in various biological phenomena, including enzyme regulation. One such enzyme is L-asparaginase, which is exploited by pathogenic microbes to cause infectious disease in humans...
October 11, 2016: Drug Discovery Today
Vitor Mendes, Tom L Blundell
Fragment-based drug discovery is now widely used in academia and industry to obtain small molecule inhibitors for a given target and is established for many fields of research including antimicrobials and oncology. Many molecules derived from fragment-based approaches are already in clinical trials and two-vemurafenib and venetoclax-are on the market, but the approach has been used sparsely in the tuberculosis field. Here, we describe the progress of our group and others, and examine the most recent successes and challenges in developing compounds with antimycobacterial activity...
October 11, 2016: Drug Discovery Today
Xiongwei Hu, Xiaochun Dong, Yi Lu, Jianping Qi, Weili Zhao, Wei Wu
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 probes should be judged crucially because images merely reflect bulk signals of an admixture of the nanoparticles and free probes. It is crucial to discriminate between nanocarrier-bound and free signals...
October 11, 2016: Drug Discovery Today
Sarwar Beg, Mahfoozur Rahman, Atul Jain, Sumant Saini, Patrick Midoux, Chantal Pichon, Farhan Jalees Ahmad, Sohail Akhter
Metal organic frameworks (MOFs), porous hybrid polymer-metal composites at the nanoscale, are recent innovations in the field of chemistry; they are novel polymeric materials with diverse biomedical applications. MOFs are nanoporous materials, consisting of metal ions linked together by organic bridging ligands. The unique physical and chemical characteristics of MOFs have attracted wider attention from the scientific community, exploring their utility in the field of material science, biology, nanotechnology and drug delivery...
October 11, 2016: Drug Discovery Today
Stuart P McElroy, Philip S Jones, Denise V Barrault
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 Sciences Alliance (SULSA) established a fund to develop assays to meet quality criteria such as those of the European Lead Factory...
October 5, 2016: Drug Discovery Today
Stewart T Cole
No abstract text is available yet for this article.
October 4, 2016: Drug Discovery Today
Katarína Mikušová, Sean Ekins
Tuberculosis drug discovery has shifted in recent years from a primarily target-based approach to one that uses phenotypic high-throughput screens. As examples of this, through our EU-funded FP7 collaborations, New Medicines for Tuberculosis was target-based and our more-recent More Medicines for Tuberculosis project predominantly used phenotypic screening. From these projects we have examples of success (DprE1) and failure (PimA) going from drug to target and from target to drug, respectively. It is clear that we still have much to learn about the drug targets and the complex effects of the drugs on Mycobacterium tuberculosis...
October 4, 2016: Drug Discovery Today
Barbara Wiśniowska, Sebastian Polak
This review aims to present and compare various Torsade de pointes propensity classification schemes of drugs that are publicly available from many scientific sources. We have also tracked and listed the compounds that were differently categorized. Additionally, we would like to draw attention to the need for establishing a general, standardized classification of a drug's proarrhythmic propensity. This is especially important in the current drug development process because of the changing paradigm of drug cardiac safety assessment...
October 4, 2016: Drug Discovery Today
Jianping Qi, Jie Zhuang, Yi Lu, Xiaochun Dong, Weili Zhao, Wei Wu
The in vivo fate of lipid-based nanoparticles (LBNs) is essentially determined by the properties of their lipid compositions. LBNs are rapidly degraded via lipolysis wherever lipases are abundant, especially in the gastrointestinal tract. LBNs that survive lipolysis can be translocated through the circulation to reach terminal organs or tissues. Lipid composition, particle size, and surface decoration, as well as the formation of protein corona, are the main factors influencing the in vivo fate of LBNs. As we discuss here, elucidation of the in vivo fate of LBNs helps weigh the balance between lipolysis and biorecognition, and is emerging as a new field of research...
October 3, 2016: Drug Discovery Today
Eugenia Gentile, Grazia M Liuzzi
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 the discovery of marine natural products with anti-MMP activities. Despite recent advances in this field, the possibility of using marine MMP inhibitors (MMPIs) for the treatment of neuroinflammation is still under-investigated...
September 30, 2016: Drug Discovery Today
Thanigaimalai Pillaiyar, Manoj Manickam, Sang-Hun Jung
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 café-au-lait macules ephelides (freckles), solar lentigo (age spots) and melasma, as well as cancer and vitiligo. Hence the regulation of melanogenesis is very important for treating hyperpigmentary disorders. Numerous antimelanogenic agents that target tyrosinase activity and/or stability, melanosome maturation, transfer and trafficking, or melanogenesis-related signaling pathways have been developed...
September 28, 2016: Drug Discovery Today
Jiange Qiu, Zhi Shi, Jianxiong Jiang
Glioblastoma multiforme (GBM) represents the most prevalent brain primary tumor, yet there is a lack of effective treatment. With current therapies, fewer than 5% of patients with GBM survive more than 5 years after diagnosis. Mounting evidence from epidemiological studies reveals that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is correlated with reduced incidence of GBM, suggesting that cyclooxygenase-2 (COX-2) and its major product within the brain, prostaglandin E2 (PGE2), are involved in the development and progression of GBM...
September 28, 2016: Drug Discovery Today
Morris Muliaditan, Geraint R Davies, Ulrika S H Simonsson, Stephen H Gillespie, Oscar Della Pasqua
Despite promising advances in the field and highly effective first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relations. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development...
September 28, 2016: Drug Discovery Today
Sarah R Mudd, Robert A Comley, Mats Bergstrom, Kyle D Holen, Yanping Luo, Sabin Carme, Gerard B Fox, Laurent Martarello, John D Beaver
Tremendous breakthroughs are being made in cancer drug discovery and development. However, such breakthroughs come at a high financial cost. At a time when there is increasing pressure on drug pricing, in part because of increased life expectancy, it is more important than ever to drive new therapeutics towards patients as efficiently as possible. In this review we discuss the applications of molecular imaging in oncology drug development, with a focus on its ability to enable better early decision making, to increase efficiency and thereby to lower costs...
September 28, 2016: Drug Discovery Today
Quentin Vanhaelen, Polina Mamoshina, Alexander M Aliper, Artem Artemov, Ksenia Lezhnina, Ivan Ozerov, Ivan Labat, Alex Zhavoronkov
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 generic modular organization of a repurposing workflow. We also review 3D structure-based, similarity-based, inference-based and machine learning (ML)-based methods. We summarize the advantages and disadvantages of these methods to emphasize three current technical challenges...
September 28, 2016: Drug Discovery Today
Adriana Isvoran, Maxime Louet, Diana Larisa Vladoiu, Dana Craciun, Marie-Anne Loriot, Bruno O Villoutreix, Maria A Miteva
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 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism...
September 28, 2016: Drug Discovery Today
Hanna Leek, Linda Thunberg, Anna C Jonson, Kristina Öhlén, Magnus Klarqvist
A strategy for large-scale chiral resolution is illustrated by the isolation of pure enantiomer from a 5kg batch. Results from supercritical fluid chromatography will be presented and compared with normal phase liquid chromatography. Solubility of the compound in the supercritical mobile phase was shown to be the limiting factor. To circumvent this, extraction injection was used but shown not to be efficient for this compound. Finally, a method for chiral resolution by crystallization was developed and applied to give diastereomeric salt with an enantiomeric excess of 99% at a 91% yield...
September 28, 2016: Drug Discovery Today
Prina Mehta, Rita Haj-Ahmad, Manoochehr Rasekh, Muhammad S Arshad, Ashleigh Smith, Susanna M van der Merwe, Xiang Li, Ming-Wei Chang, Zeeshan Ahmad
Complex micro- and nano-structures enable crucial developments in the healthcare remit (e.g., pharmaceutical and biomaterial sciences). In recent times, several technologies have been developed and explored to address key healthcare challenges (e.g., advanced chemotherapy, biomedical diagnostics and tissue regeneration). Electrohydrodynamic atomization (EHDA) technologies are rapidly emerging as promising candidates to address these issues. The fundamental principle driving EHDA engineering relates to the action of an electric force (field) on flowing conducting medium (formulation) giving rise to a stable Taylor cone...
September 28, 2016: Drug Discovery Today
Harshali Patil, Shailaja Gada Saxena, Colin J Barrow, Jagat R Kanwar, Arnab Kapat, Rupinder K Kanwar
Colorectal cancer (CRC) is a major health burden worldwide. The optimal approach to the diagnosis, management, and treatment of CRC involves multidisciplinary and integrated management practices. The field is rapidly changing because of recent advancements in delineating the molecular basis of tumorigenesis, introduction of targeted therapy, varied patient response to mainstay chemotherapeutics, biological drugs, and the effective combination regimes being used for treatment. Recent meta-analysis studies, which tend to establish few clinically useful predictor biomarkers, identify inconsistent results and limitations of the trials...
September 28, 2016: Drug Discovery Today
Ashok Kumar Sharma, Avinash Gothwal, Prashant Kesharwani, Hashem Alsaab, Arun K Iyer, Umesh Gupta
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 encapsulation, and solubilizing and passive targeting also equally contribute to the therapeutic use of dendrimers. In this review, we highlight recent advances in the delivery of anticancer drugs using dendrimers, as well as other biomedical and diagnostic applications...
September 23, 2016: Drug Discovery Today
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