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Drug Discovery Today

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https://www.readbyqxmd.com/read/29792929/recent-advances-in-intra-articular-drug-delivery-systems-for-osteoarthritis-therapy
#1
REVIEW
Pierre Maudens, Olivier Jordan, Eric Allémann
Osteoarthritis (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...
May 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29778697/structural-basis-for-selective-inhibition-of-antibacterial-target-mray-a-membrane-bound-enzyme-involved-in-peptidoglycan-synthesis
#2
REVIEW
Jenny Hering, Elin Dunevall, Margareta Ek, Gisela Brändén
The 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)...
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29778696/renal-pre-competitive-consortium-rpc-2-discovering-therapeutic-targets-together
#3
Mark Tomilo, Heather Ascani, Barbara Mirel, Maria Chiara Magnone, Carol Moreno Quinn, Anil Karihaloo, Kevin Duffin, Uptal D Patel, Matthias Kretzler
Despite 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...
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29778695/corticosteroids-and-perinatal-hypoxic-ischemic-brain-injury
#4
REVIEW
Katherine R Concepcion, Lubo Zhang
Perinatal 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...
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29778694/bioorthogonal-chemistry-in-bioluminescence-imaging
#5
Aurélien Godinat, Arkadiy A Bazhin, Elena A Goun
Bioorthogonal 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.
May 17, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29775669/nanogels-as-potential-drug-nanocarriers-for-cns-drug-delivery
#6
REVIEW
Arti Vashist, Ajeet Kaushik, Atul Vashist, Jyoti Bala, Roozbeh Nikkhah-Moshaie, Vidya Sagar, Madhavan Nair
Hydrogel-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)...
May 15, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29775668/current-approaches-to-the-discovery-of-novel-inhaled-medicines
#7
REVIEW
Peter Strong, Kazuhiro Ito, John Murray, Garth Rapeport
Inhaled 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...
May 15, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29772209/prolyl-hydroxylase-2-a-promising-target-to-inhibit-hypoxia-induced-cellular-metabolism-in-cancer-cells
#8
REVIEW
Lakhveer Singh, Sara Aldosary, Abdulaziz S Saeedan, M Nazam Ansari, Gaurav Kaithwas
Hypoxia-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...
May 14, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29758342/next-generation-sequencing-in-drug-development-target-identification-and-genetically-stratified-clinical-trials
#9
REVIEW
Abolfazl Doostparast Torshizi, Kai Wang
Next-generation sequencing (NGS) enabled high-throughput analysis of genotype-phenotype relationships on human populations, ushering in a new era of genetics-informed drug development. The year 2017 was remarkable, with the first FDA-approved gene therapy for cancer (Kymriah™) and for inherited diseases (LUXTURNA™), the first multiplex NGS panel for companion diagnostics (MSK-IMPACT™) and the first drug targeting a genetic signature rather than a disease (Keytruda® ). We envision that population-scale NGS with paired electronic health records (EHRs) will become a routine measure in the drug development process for the identification of novel drug targets, and that genetically stratified clinical trials could be widely adopted to improve power in precision-medicine-guided drug development...
May 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29753878/targeting-hif-2%C3%AE-as-therapy-for-advanced-cancers
#10
REVIEW
Thanabal Murugesan, Gurukumari Rajajeyabalachandran, Swetha Kumar, Shruthi Nagaraju, Sooriya Kumar
Hypoxia-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...
May 10, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29753124/translation-of-innovative-chemistry-into-screening-libraries-an-exemplar-partnership-from-the-european-lead-factory
#11
Remy Morgentin, Mark Dow, Anthony Aimon, George Karageorgis, Tuomo Kalliokoski, Didier Roche, Stephen Marsden, Adam S Nelson
The 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...
May 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29751111/2017-in-review-fda-approvals-of-new-molecular-entities
#12
Michael S Kinch, Rebekah H Griesenauer
An overview of drugs approved by the FDA in 2017 reflected a reversion to the mean after a low number of NME approvals in 2016. This reversal was largely driven by the largest number of biologics-based NMEs recorded to date, which offset an average number of small-molecule approvals. Oncology indications continued to dominate followed by novel treatments for infectious, immunologic and neurologic diseases. From a mechanistic standpoint, the industry has continued a trend of target diversification, reflecting advances in scientific understanding of disease processes...
May 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29750903/targeting-cancer-metabolism-to-develop-human-lactate-dehydrogenase-hldh-5-inhibitors
#13
REVIEW
Shao-Lin Zhang, Yun He, Kin Yip Tam
Cancer 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...
May 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29750902/machine-learning-in-chemoinformatics-and-drug-discovery
#14
REVIEW
Yu-Chen Lo, Stefano E Rensi, Wen Torng, Russ B Altman
Chemoinformatics 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...
May 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29747006/bioinspired-bone-therapies-using-naringin-applications-and-advances
#15
REVIEW
Pedro Lavrador, Vitor M Gaspar, João F Mano
The 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...
May 7, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29747005/is-the-adenosine-a-2b-biased-receptor-a-valuable-target-for-the-treatment-of-pulmonary-arterial-hypertension
#16
REVIEW
Mafalda Bessa-Gonçalves, Bruno Bragança, Eduardo Martins-Dias, Paulo Correia-de-Sá, Ana Patrícia Fontes-Sousa
Pulmonary 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 A2B AR 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...
May 7, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29747004/real-world-evidence-approach-to-traditional-herbal-medicinal-products
#17
EDITORIAL
Xinyu Weng
There 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...
May 7, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29747003/the-extent-and-effects-of-patient-involvement-in-pictogram-design-for-written-drug-information-a-short-systematic-review
#18
REVIEW
Mara M van Beusekom, Anne H Kerkhoven, Mark J W Bos, Henk-Jan Guchelaar, Jos M van den Broek
This 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...
May 7, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29747002/dual-therapy-strategy-for-modification-of-adiponectin-receptor-signaling-in-aging-associated-chronic-diseases
#19
REVIEW
Masaaki Waragai, Gilbert Ho, Yoshiki Takamatsu, Yuka Shimizu, Hiromu Sugino, Shuei Sugama, Takato Takenouchi, Eliezer Masliah, Makoto Hashimoto
Given 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...
May 7, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29738823/when-fragments-link-a-bibliometric-perspective-on-the-development-of-fragment-based-drug-discovery
#20
REVIEW
Angelo K S Romasanta, Peter van der Sijde, Iina Hellsten, Roderick E Hubbard, Gyorgy M Keseru, Jacqueline van Muijlwijk-Koezen, Iwan J P de Esch
Fragment-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...
May 5, 2018: Drug Discovery Today
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