Drugp-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management.
Abstract Drug-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; postmark...
Source: Drug Discovery Today - June 11, 2018 Category: Drugs & Pharmacology Authors: Wen Z, Liang Y, Hao Y, Delavan B, Huang R, Mikailov M, Tong W, Li M, Liu Z Tags: Drug Discov Today Source Type: research

Why are there no drugs indicated for sciatica, the most common chronic neuropathic syndrome of all?
Abstract Here, we examine 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 o...
Source: Drug Discovery Today - June 9, 2018 Category: Drugs & Pharmacology Authors: Markman JD, Baron R, Gewandter JS Tags: Drug Discov Today Source Type: research

The fruit fly Drosophila melanogaster as an innovative preclinical ADME model for solute carrier membrane transporters, with consequences for pharmacology and drug therapy.
Abstract Solute 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 ...
Source: Drug Discovery Today - June 8, 2018 Category: Drugs & Pharmacology Authors: Wang Y, Moussian B, Schaeffeler E, Schwab M, Nies AT Tags: Drug Discov Today Source Type: research

Therapeutic application of antibody fragments in autoimmune diseases: current state and prospects.
Abstract Over 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 ...
Source: Drug Discovery Today - June 8, 2018 Category: Drugs & Pharmacology Authors: Fernandes JC Tags: Drug Discov Today Source Type: research

Interrogating the microbiome: experimental and computational considerations in support of study reproducibility.
eng J Abstract The 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...
Source: Drug Discovery Today - June 8, 2018 Category: Drugs & Pharmacology Authors: Poussin C, Sierro N, Boué S, Battey J, Scotti E, Belcastro V, Peitsch MC, Ivanov NV, Hoeng J Tags: Drug Discov Today Source Type: research

Translational strategy: humanized mini-organs.
Abstract Mini-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...
Source: Drug Discovery Today - June 5, 2018 Category: Drugs & Pharmacology Authors: Nguyen DT, Althage M, Magnone MC, Heydarkhan-Hagvall S Tags: Drug Discov Today Source Type: research

Supermolecular drug challenge to overcome drug resistance in cancer cells.
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 supramolecular 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. PMID: 29879476 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 4, 2018 Category: Drugs & Pharmacology Authors: Onishi Y, Eshita Y, Ji RC, Kobayashi T, Onishi M, Mizuno M, Yoshida J, Kubota N Tags: Drug Discov Today Source Type: research

Advances in treatment formulations for acute myeloid leukemia.
rce F Abstract Acute myeloid leukemia (AML) is the most common cause of leukemia-related mortality. The combination of cytarabine and anthracycline has been the gold standard of treatment over the past 40 years, but the distribution of the drugs in the body leads to severe adverse effects. Poor prognosis of older patients with AML is the consequence not only of comorbidities, but also of chemoresistance resulting from frequent secondary AML. Numerous strategies using nanotechnologies are in development to improve drug targeting, pharmacokinetics, administration route, chemoresistance, and adverse effects generally...
Source: Drug Discovery Today - June 2, 2018 Category: Drugs & Pharmacology Authors: Briot T, Roger E, Thépot S, Lagarce F Tags: Drug Discov Today Source Type: research

Recommendations toward a human pathway-based approach to disease research.
Abstract Failures 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 increa...
Source: Drug Discovery Today - June 2, 2018 Category: Drugs & Pharmacology Authors: Marshall LJ, Austin CP, Casey W, Fitzpatrick SC, Willett C Tags: Drug Discov Today Source Type: research

Why breast cancer signatures are no better than random signatures.
Abstract Random 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 effe...
Source: Drug Discovery Today - June 1, 2018 Category: Drugs & Pharmacology Authors: Goh WWB, Wong L Tags: Drug Discov Today Source Type: research

Bioinformatics-based tools in drug discovery: the cartography from single gene to integrative biological networks.
Abstract Originally 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 belie...
Source: Drug Discovery Today - June 1, 2018 Category: Drugs & Pharmacology Authors: Ramharack P, Soliman MES Tags: Drug Discov Today Source Type: research

Deubiquitinating enzymes in cancer stem cells: functions and targeted inhibition for cancer therapy.
Abstract The 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 th...
Source: Drug Discovery Today - June 1, 2018 Category: Drugs & Pharmacology Authors: Kaushal K, Antao AM, Kim KS, Ramakrishna S Tags: Drug Discov Today Source Type: research

Mesenteric ischemia-reperfusion: an overview of preclinical drug strategies.
Abstract Mesenteric 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 preclinic...
Source: Drug Discovery Today - May 29, 2018 Category: Drugs & Pharmacology Authors: Bertoni S, Ballabeni V, Barocelli E, Tognolini M Tags: Drug Discov Today Source Type: research

Lipid-polymer hybrid nanocarrier-mediated cancer therapeutics: current status and future directions.
Abstract Here, we review methods for enhancing the targeting efficiency and applications of LPHNPs. The novel formulations of LPHNPs have shown promising results for the targeted delivery of methotrexate to address rheumatoid arthritis and cancer. PMID: 29857164 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 29, 2018 Category: Drugs & Pharmacology Authors: Garg NK, Tandel N, Jadon RS, K Tyagi R, Katare OP Tags: Drug Discov Today Source Type: research

microRNAs and cardiac stem cells in heart development and disease.
Abstract Cumulative 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 h...
Source: Drug Discovery Today - May 28, 2018 Category: Drugs & Pharmacology Authors: Li B, Meng X, Zhang L Tags: Drug Discov Today Source Type: research

Drug metabolism and pharmacokinetic strategies for oligonucleotide- and mRNA-based drug development.
f L Abstract Oligonucleotide 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 P...
Source: Drug Discovery Today - May 28, 2018 Category: Drugs & Pharmacology Authors: Andersson S, Antonsson M, Elebring M, Jansson-Löfmark R, Weidolf L Tags: Drug Discov Today Source Type: research

Is the independence of medical research at stake? On the forces shaping the research agenda.
PMID: 29842937 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 26, 2018 Category: Drugs & Pharmacology Authors: Anderlini D Tags: Drug Discov Today Source Type: research

Bioactive glasses entering the mainstream.
Abstract Over 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...
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Kargozar S, Baino F, Hamzehlou S, Hill RG, Mozafari M Tags: Drug Discov Today Source Type: research

Reshaping drug development using 3D printing.
Abstract The 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 ...
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Awad A, Trenfield SJ, Goyanes A, Gaisford S, Basit AW Tags: Drug Discov Today Source Type: research

Progress in the development of nanosensitizers for X-ray-induced photodynamic therapy.
Abstract In 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 developme...
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Ren XD, Hao XY, Li HC, Ke MR, Zheng BY, Huang JD Tags: Drug Discov Today Source Type: research

The Clinical Innovation Network: a policy for promoting development of drugs and medical devices in Japan.
Abstract The continuous increase in the costs of developing new drugs and medical devices drives increases in medical expenses. Seventy to ninety percent of these costs are associated with clinical trials. Therefore, the development of cost-effective methods to perform clinical trials remains a challenge. One approach is to use patient registries, collections of data related to patients with a specific diagnosis, condition, or procedure. Patient registries are used in Denmark, Sweden, and the USA for the enrollment of patients into clinical trials, and to evaluate endpoints. In Japan, a national project for regist...
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Matsushita S, Tachibana K, Kondoh M Tags: Drug Discov Today Source Type: research

Host-defense peptides and their potential use as biomarkers in human diseases.
Abstract Since the early 19th century, it has been known that host-defense peptides (HDPs) have a crucial role in innate host defense. Subsequent work has demonstrated their role in adaptive immunity as well as their involvement in different inflammatory diseases, autoimmune diseases, and cancer. 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 biomarker of such diseases. Thus, research has aimed to validate the clinical use of HDPs for diagnosis, prognosis, and further treatment....
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Silva ON, Porto WF, Ribeiro SM, Batista I, Franco OL Tags: Drug Discov Today Source Type: research

Understanding drug targets: no such thing as bad news.
Abstract How 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 targ...
Source: Drug Discovery Today - May 24, 2018 Category: Drugs & Pharmacology Authors: Roberts RA Tags: Drug Discov Today Source Type: research

Recent advances in intra-articular drug delivery systems for osteoarthritis therapy.
ann E Abstract 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. This paper reviews the role and interaction among diffe...
Source: Drug Discovery Today - May 21, 2018 Category: Drugs & Pharmacology Authors: Maudens P, Jordan O, Allémann E Tags: Drug Discov Today Source Type: research

Bioorthogonal chemistry in bioluminescence imaging.
Abstract 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. PMID: 29778694 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 17, 2018 Category: Drugs & Pharmacology Authors: Godinat A, Bazhin AA, Goun EA Tags: Drug Discov Today Source Type: research

Corticosteroids and perinatal hypoxic-ischemic brain injury.
Abstract 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 b...
Source: Drug Discovery Today - May 17, 2018 Category: Drugs & Pharmacology Authors: Concepcion KR, Zhang L Tags: Drug Discov Today Source Type: research

Renal Pre-Competitive Consortium (RPC2): discovering therapeutic targets together.
Abstract 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 identifica...
Source: Drug Discovery Today - May 17, 2018 Category: Drugs & Pharmacology Authors: Tomilo M, Ascani H, Mirel B, Magnone MC, Quinn CM, Karihaloo A, Duffin K, Patel UD, Kretzler M Tags: Drug Discov Today Source Type: research

Structural basis for selective inhibition of antibacterial target MraY, a membrane-bound enzyme involved in peptidoglycan synthesis.
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. PMID: 29778697 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 17, 2018 Category: Drugs & Pharmacology Authors: Hering J, Dunevall E, Ek M, Brändén G Tags: Drug Discov Today Source Type: research

Current approaches to the discovery of novel inhaled medicines.
Abstract 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 drug...
Source: Drug Discovery Today - May 15, 2018 Category: Drugs & Pharmacology Authors: Strong P, Ito K, Murray J, Rapeport G Tags: Drug Discov Today Source Type: research

Nanogels as potential drug nanocarriers for CNS drug delivery.
Abstract 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). We also discuss the...
Source: Drug Discovery Today - May 15, 2018 Category: Drugs & Pharmacology Authors: Vashist A, Kaushik A, Vashist A, Bala J, Nikkhah-Moshaie R, Sagar V, Nair M Tags: Drug Discov Today Source Type: research

Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced cellular metabolism in cancer cells.
Abstract 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 ...
Source: Drug Discovery Today - May 14, 2018 Category: Drugs & Pharmacology Authors: Singh L, Aldosary S, Saeedan AS, Ansari MN, Kaithwas G Tags: Drug Discov Today Source Type: research

Next-generation sequencing in drug development: target identification and genetically stratified clinical trials.
Abstract 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 th...
Source: Drug Discovery Today - May 11, 2018 Category: Drugs & Pharmacology Authors: Torshizi AD, Wang K Tags: Drug Discov Today Source Type: research

Targeting HIF-2 α as therapy for advanced cancers.
Targeting HIF-2α as therapy for advanced cancers. Drug Discov Today. 2018 May 10;: Authors: Murugesan T, Rajajeyabalachandran G, Kumar S, Nagaraju S, Kumar S Abstract 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....
Source: Drug Discovery Today - May 10, 2018 Category: Drugs & Pharmacology Authors: Murugesan T, Rajajeyabalachandran G, Kumar S, Nagaraju S, Kumar S Tags: Drug Discov Today Source Type: research

Translation of innovative chemistry into screening libraries: an exemplar partnership from the European Lead Factory.
Abstract 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. The partnership could serve as a blueprint for the translatio...
Source: Drug Discovery Today - May 9, 2018 Category: Drugs & Pharmacology Authors: Morgentin R, Dow M, Aimon A, Karageorgis G, Kalliokoski T, Roche D, Marsden S, Nelson AS Tags: Drug Discov Today Source Type: research

Machine learning in chemoinformatics and drug discovery.
Abstract 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 QSA...
Source: Drug Discovery Today - May 8, 2018 Category: Drugs & Pharmacology Authors: Lo YC, Rensi SE, Torng W, Altman RB Tags: Drug Discov Today Source Type: research

Targeting cancer metabolism to develop human lactate dehydrogenase (hLDH)5 inhibitors.
Abstract 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. Here, we briefly discuss the roles of hLDH5 and its connections with cancer metabolism. Then,...
Source: Drug Discovery Today - May 8, 2018 Category: Drugs & Pharmacology Authors: Zhang SL, He Y, Tam KY Tags: Drug Discov Today Source Type: research

2017 in review: FDA approvals of new molecular entities.
Abstract 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. Finally, 2017 continued a period of rel...
Source: Drug Discovery Today - May 8, 2018 Category: Drugs & Pharmacology Authors: Kinch MS, Griesenauer RH Tags: Drug Discov Today Source Type: research

Dual-therapy strategy for modification of adiponectin receptor signaling in aging-associated chronic diseases.
Abstract 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. Thus, distinct from metabolic syndrome, it is anti...
Source: Drug Discovery Today - May 7, 2018 Category: Drugs & Pharmacology Authors: Waragai M, Ho G, Takamatsu Y, Shimizu Y, Sugino H, Sugama S, Takenouchi T, Masliah E, Hashimoto M Tags: Drug Discov Today Source Type: research

The extent and effects of patient involvement in pictogram design for written drug information: a short systematic review.
Abstract 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. Repeated involvement of (non-)patients aids the design of effective pharmace...
Source: Drug Discovery Today - May 7, 2018 Category: Drugs & Pharmacology Authors: Beusekom MMV, Kerkhoven AH, Bos MJW, Guchelaar HJ, Broek JMVD Tags: Drug Discov Today Source Type: research

Real-world evidence approach to traditional herbal medicinal products.
Abstract 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. Different regulatory approaches reflect diff...
Source: Drug Discovery Today - May 7, 2018 Category: Drugs & Pharmacology Authors: Weng X Tags: Drug Discov Today Source Type: research

Is the adenosine A2B 'biased' receptor a valuable target for the treatment of pulmonary arterial hypertension?
, Fontes-Sousa AP Abstract 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 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' recepto...
Source: Drug Discovery Today - May 7, 2018 Category: Drugs & Pharmacology Authors: Bessa-Gonçalves M, Bragança B, Martins-Dias E, Correia-de-Sá P, Fontes-Sousa AP Tags: Drug Discov Today Source Type: research

Bioinspired bone therapies using naringin: applications and advances.
Abstract 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. The topic is discussed in light of recently develo...
Source: Drug Discovery Today - May 7, 2018 Category: Drugs & Pharmacology Authors: Lavrador P, Gaspar VM, Mano JF Tags: Drug Discov Today Source Type: research

When fragments link: a bibliometric perspective on the development of fragment-based drug discovery.
This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields. PMID: 29738823 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 5, 2018 Category: Drugs & Pharmacology Authors: Romasanta AKS, van der Sijde P, Hellsten I, Hubbard RE, Keseru GM, van Muijlwijk-Koezen J, de Esch IJP Tags: Drug Discov Today Source Type: research

Applying the 3Rs to neuroscience research involving nonhuman primates.
Abstract This Feature focuses on UK neuroscience research using nonhuman primates (NHPs), and the application of the 3Rs, in the light of the recent EU SCHEER report and subsequent article by Prescott et al. The challenge of understanding the human brain and its disorders means that NHP research is still very much needed, although it is essential that this research is complemented by studies using other approaches, such as human volunteers and patients, and other alternatives to NHP use. Analysis of recent publications shows that these complementary approaches are already being actively exploited by NHP researcher...
Source: Drug Discovery Today - May 4, 2018 Category: Drugs & Pharmacology Authors: Lemon RN Tags: Drug Discov Today Source Type: research

Cochlear hair cell regeneration: an emerging opportunity to cure noise-induced sensorineural hearing loss.
Abstract In 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, much research is focusing 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 progress in restoring the sensory epithelium after SNHL resulting from noise exposure. The prevalent strategy to regenerate cochlear hair cel...
Source: Drug Discovery Today - May 4, 2018 Category: Drugs & Pharmacology Authors: Youm I, Li W Tags: Drug Discov Today Source Type: research

Protein-peptide docking: opportunities and challenges.
Abstract Peptides 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 a...
Source: Drug Discovery Today - May 4, 2018 Category: Drugs & Pharmacology Authors: Ciemny M, Kurcinski M, Kamel K, Kolinski A, Alam N, Schueler-Furman O, Kmiecik S Tags: Drug Discov Today Source Type: research

Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes.
Abstract Long 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 ...
Source: Drug Discovery Today - April 23, 2018 Category: Drugs & Pharmacology Authors: Tripathi MK, Doxtater K, Keramatnia F, Zacheaus C, Yallapu MM, Jaggi M, Chauhan SC Tags: Drug Discov Today Source Type: research

Cyclodextrins as excipients in tablet formulations.
M, Lobo JMS Abstract This 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 effic...
Source: Drug Discovery Today - April 21, 2018 Category: Drugs & Pharmacology Authors: Conceição J, Adeoye O, Cabral-Marques HM, Lobo JMS Tags: Drug Discov Today Source Type: research

Novel Nanotherapeutic Strategies: Fabrication Approaches, Application and Clinical Challenges.
PMID: 29674219 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - April 16, 2018 Category: Drugs & Pharmacology Authors: Agrahari V, Agrahari V Tags: Drug Discov Today Source Type: research

Cancer theranostic applications of lipid-based nanoparticles.
Abstract A variety of nanoplatforms have been developed and applied for cancer therapy, imaging, or the combination thereof. These nanoplatforms, combined with therapeutic and imaging functionalities, display great potential to enhance medical care. In particular, lipid-based nanoparticles (LNPs) are among the most-studied platforms that have resulted in many encouraging advances in theranostics. LNPs are biodegradable and biocompatible, and their formulation can be tailored for various applications. Here, we provide an overview of recent developments of four representative LNP platforms for theranostics: stealth ...
Source: Drug Discovery Today - April 13, 2018 Category: Drugs & Pharmacology Authors: Tang WL, Tang WH, Li SD Tags: Drug Discov Today Source Type: research