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Drug Discovery Today

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https://www.readbyqxmd.com/read/29339107/influenza-a-virus-polymerase-an-attractive-target-for-next-generation-anti-influenza-therapeutics
#1
REVIEW
Zhongxia Zhou, Tao Liu, Jian Zhang, Peng Zhan, Xinyong Liu
The influenza RNA-dependent RNA polymerase (RdRP) is conserved among different types of influenza virus, playing an important part in transcription and replication. In this regard, influenza RdRP is an attractive target for novel anti-influenza drug discovery. Herein, we will introduce the structural and functional information of influenza polymerase; and an overview of inhibitors targeting the PA endonuclease and PB2 cap-binding site is provided, along with the approaches utilized for identification of these inhibitors...
January 12, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29339106/safinamide-a-new-hope-for-parkinson-s-disease
#2
REVIEW
Fábio G Teixeira, Miguel F Gago, Paulo Marques, Pedro Silva Moreira, Ricardo Magalhães, Nuno Sousa, António J Salgado
The loss of dopaminergic neurons (DAn) and reduced dopamine (DA) production underlies the reasoning behind the gold standard treatment for Parkinson's disease (PD) using levodopa (L-DOPA). Recently licensed by the European Medicine Agency (EMA) and US Food and Drug Administration (FDA), safinamide [a monoamine oxidase B (MOA-B) inhibitor] is an alternative to L-DOPA; as we discuss here, it enhances dopaminergic transmission with decreased secondary effects compared with L-DOPA. In addition, nondopaminergic actions (neuroprotective effects) have been reported, with safinamide inhibiting glutamate release and sodium/calcium channels, reducing the excitotoxic input to dopaminergic neuronal death...
January 12, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337205/increasing-mtdna-levels-as-therapy-for-mitochondrial-optic-neuropathies
#3
Eduardo Ruiz-Pesini, Sonia Emperador, Ester López-Gallardo, Carmen Hernandez-Ainsa, Julio Montoya
Leber hereditary optic neuropathy (LHON) is a rare, inherited mitochondrial disease. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. Primary open-angle glaucoma is a frequent, acquired optic neuropathy. Lowering intraocular pressure reduces disease progression. However, current methods to decelerate this progression are recognized as being inadequate. Therefore, there is a clear need to look for new therapeutic approaches. The growing evidence indicates that primary open-angle glaucoma can also be a mitochondrial optic neuropathy (MON)...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337204/the-positive-impacts-of-real-world-data-on-the-challenges-facing-the-evolution-of-biopharma
#4
REVIEW
John Wise, Angeli Möller, David Christie, Dipak Kalra, Elia Brodsky, Evelina Georgieva, Greg Jones, Ian Smith, Lars Greiffenberg, Marie McCarthy, Michael Arend, Olivier Luttringer, Sebastian Kloss, Steve Arlington
Demand for healthcare services is unprecedented. Society is struggling to afford the cost. Pricing of biopharmaceutical products is under scrutiny, especially by payers and Health Technology Assessment agencies. As we discuss here, rapidly advancing technologies, such Real-World Data (RWD), are being utilized to increase understanding of disease. RWD, when captured and analyzed, produces the Real-World Evidence (RWE) that underpins the economic case for innovative medicines. Furthermore, RWD can inform the understanding of disease, help identify new therapeutic intervention points, and improve the efficiency of research and development (R&D), especially clinical trials...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337203/stem-cells-as-vehicles-and-targets-of-nanoparticles
#5
REVIEW
Sónia Pinho, Maria H Macedo, Catarina Rebelo, Bruno Sarmento, Lino Ferreira
Modulation of endogenous adult stem cell niches represents a promising strategy for regeneration of tissues and to correct cell abnormalities, including cancer. Recent advances show the possibility to target endogenous stem cells or their progenies by using nanoparticles conjugated with specific biomolecules. In addition, the targeting of the stem cell niche can be accomplished by using stem cells loaded with nanoparticles. This review examines principles for the targeting of endogenous stem cells as well as factors for the modulation of stem cells...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337202/progress-with-covalent-small-molecule-kinase-inhibitors
#6
REVIEW
Zheng Zhao, Philip E Bourne
With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens of structural system pharmacology, here we review this rapid progress by considering design strategies and the challenges and opportunities offered by current CSKIs.
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337201/on-the-glycosylation-aspects-of-biosimilarity
#7
REVIEW
László Hajba, Ákos Szekrényes, Beáta Borza, András Guttman
The recent expiration of several protein therapeutics opened the door for biosimilar development. Biosimilars are biologic medical products that are similar but not identical copies of already-authorized protein therapeutics. Critical quality attributes (CQA), such as post-translational modifications of recombinant biotherapeutics, are important for the clinical efficacy and safety of both the innovative biologics and their biosimilar counterparts. Here, we summarize biosimilarity CQAs, considering the regulatory guidelines and the statistical aspects (e...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337200/mimicking-the-3d-biology-of-osteochondral-tissue-with-microfluidic-based-solutions-breakthroughs-towards-boosting-drug-testing-and-discovery
#8
REVIEW
Mariana R Carvalho, Rui Luís Reis, Joaquim Miguel Oliveira
The development of tissue-engineering (TE) solutions for osteochondral (OC) regeneration has been slowed by technical hurdles related to the recapitulation of their complex and hierarchical architecture. OC defects refer to damage of both the articular cartilage and the underlying subchondral bone. To repair an OC tissue defect, the complexity of the bone and cartilage must be considered. To help achieve this, microfluidics is converging with TE approaches to provide new treatment possibilities. Microfluidics uses precise micrometer-to-millimeter-scale fluid flows to achieve high-resolution and spatial and/or temporal control of the cell microenvironment, providing powerful tools for cell culturing...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29337199/designing-an-intuitive-web-application-for-drug-discovery-scientists
#9
Nikiforos Karamanis, Miguel Pignatelli, Denise Carvalho-Silva, Francis Rowland, Jennifer A Cham, Ian Dunham
Here, we 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...
January 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29331501/incorporating-upper-motor-neuron-health-in-als-drug-discovery
#10
REVIEW
Ina Dervishi, P Hande Ozdinler
Amyotrophic lateral sclerosis (ALS) is a complex disease, affecting the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years, edaravone was recently approved as the second drug for ALS. This generated excitement in the field and revealed the need to improve preclinical assays for continued success. Here, we focus on the importance and relevance of upper motor neuron (UMN) pathology in ALS, and discuss how incorporation of UMN survival in preclinical assays will improve inclusion criteria for clinical trials and expedite the drug discovery effort in ALS and related motor neuron diseases...
January 10, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29331500/peripheral-modulation-of-the-endocannabinoid-system-in-metabolic-disease
#11
REVIEW
Nirajan Shrestha, James S M Cuffe, Dana S Hutchinson, John P Headrick, Anthony V Perkins, Andrew J McAinch, Deanne H Hryciw
Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB1) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB2) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB1 reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease...
January 10, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330127/present-drug-likeness-filters-in-medicinal-chemistry-during-the-hit-and-lead-optimization-process-how-far-can-they-be-simplified
#12
REVIEW
Serge Mignani, João Rodrigues, Helena Tomas, Rachid Jalal, Parvinder Pal Singh, Jean-Pierre Majoral, Ram A Vishwakarma
During the past decade, decreasing the attrition rate of drug development candidates reaching the market has become one of the major challenges in pharmaceutical research and drug development (R&D). To facilitate the decision-making process, and to increase the probability of rapidly finding and developing high-quality compounds, a variety of multiparametric guidelines, also known as rules and ligand efficiency (LE) metrics, have been developed. However, what are the 'best' descriptors and how far can we simplify these drug-likeness prediction tools in terms of the numerous, complex properties that they relate to?...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330126/recent-progress-in-the-discovery-of-myeloid-differentiation-2-md2-modulators-for-inflammatory-diseases
#13
REVIEW
Lingfeng Chen, Weitao Fu, Lulu Zheng, Yi Wang, Guang Liang
Myeloid 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...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330125/the-hitchhiker-s-guide-to-the-chemical-biological-galaxy
#14
REVIEW
Giulia Opassi, Alessandro Gesù, Alberto Massarotti
We are used to considering chemical and biological spaces as two different entities; although they represent a more-interconnected world, in fact they represent a Yin-Yang concept in drug discovery. Chemical-biological space is as vast as the universe and, as Douglas Adams famously said, 'Space is big. You just won't believe how vastly, hugely, mind-bogglingly big it is'. However, many researchers are convinced that it is not so infinite, and are designing computational and experimental tools to help identify and explore all possible chemical-biological space...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330124/manipulating-the-epigenome-for-the-treatment-of-disorders-with-thrombotic-complications
#15
REVIEW
Faith A A Kwa, Denise E Jackson
The haemostatic system is tightly regulated to maintain homeostasis to avoid unwanted bleeding or thrombotic complications. Recent research has highlighted the importance of epigenetic changes, such as DNA methylation, histone modifications, and miRNA-based mechanisms, that alter gene expression. This can give rise to dysregulated haemostatic or vascular expressed molecules contributing to the development of thrombotic complications. Targeting these epigenetic changes could provide a new avenue for the treatment of pathological blood clots...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330123/a-bibliometric-review-of-drug-repurposing
#16
REVIEW
Nancy C Baker, Sean Ekins, Antony J Williams, Alexander Tropsha
We have conducted a bibliometric review of drug repurposing by scanning >25 million papers in PubMed and using text-mining methods to gather, count and analyze chemical-disease therapeutic relationships. We find that >60% of the ∼35 000 drugs or drug candidates identified in our study have been tried in more than one disease, including 189 drugs that have been tried in >300 diseases each. Whereas in the majority of cases these drugs were applied in therapeutic areas close to their original use, there have been striking, and perhaps instructive, successful attempts of drug repurposing for unexpected, novel therapeutic areas...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330122/privileged-portal-metastasis-of-hepatocellular-carcinoma-in-light-of-the-coevolution-of-a-visceral-portal-system-and-liver-in-the-chordate-lineage-a-search-for-therapeutic-targets
#17
REVIEW
Vladimir M Subbotin
Hepatocellular carcinoma (HCC) disseminates systemically, but metastases occur in distant organs in only a few patients, whereas HCC routinely metastasizes to liver and its vessels. HCC cells disseminate via hepatic veins, but portal veins are affected by metastasis more frequently than are hepatic veins, and correlates with poor prognosis. In this review, I suggest that privileged HCC portal metastasis occurs because of high levels of pancreatic family hormones and growth factors (PHGFs) in the portal blood...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330121/using-network-based-expert-engagement-to-advance-pharmaceutical-research-and-development
#18
EDITORIAL
Rebecca Ashkenazy
No abstract text is available yet for this article.
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29330120/an-update-on-the-role-of-nanovehicles-in-nose-to-brain-drug-delivery
#19
REVIEW
Yunhai Feng, Haisheng He, Fengqian Li, Yi Lu, Jianping Qi, Wei Wu
A quantitative analysis has cast doubt over the limited advantages provided by particles for nose-to-brain (NTB) drug delivery. Thus, it is imperative to identify the role of nanovehicles in NTB drug delivery. If nanocarriers are used merely as an option to improve various properties of the drugs or the formulations, it is difficult for them to outperform conventional formulations, such as solutions or gels. However, nanovehicles bring about special features, such as maintenance of the solubilized state of drugs, sustained or delayed release, and enhanced penetration because of surface modifications, all of which lead to enhanced NTB delivery efficiency...
January 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29326083/ligandomics-a-paradigm-shift-in-biological-drug-discovery
#20
REVIEW
Wei Li, Iok-Hou Pang, Mario Thiego F Pacheco, Hong Tian
As productivity of pharmaceutical research and development (R&D) for small-molecule drugs declines, the trend in drug discovery strategies is shifting towards biologics, which predominantly target secreted or cell surface proteins. Receptors and ligands are the most-valuable drug targets. In contrast to conventional approaches of discovering one ligand at a time, the emerging technology of ligandomics can systematically map disease-selective cellular ligands in the absence of molecular probes. Biologics targeting these ligands with disease selectivity have the advantages of high efficacy, minimal adverse effects, wide therapeutic indices, and low safety-related attrition rates...
January 8, 2018: Drug Discovery Today
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