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Drug Discovery Today

Guorui Jin, Xin Zhao, Feng Xu
No abstract text is available yet for this article.
August 10, 2017: Drug Discovery Today
Rhys D O Jones, Marie Cooke, James Hinchliffe, Justin Morley, Simon T Barry
In vivo models have been crucial for developing our understanding of key processes associated with human disease and developing novel therapeutics. These in vivo studies are becoming increasingly complex, requiring long-term efficacy data and additional supportive datasets such as pharmacokinetic profiles and analysis of multiple biomarkers of pharmacodynamic response and efficacy. Moreover, a new agent will be investigated in many different models and often in combination with other drugs. Despite advances across the industry integrating and analysing complex datasets, management of in vivo data remains an ongoing challenge across the industry...
August 9, 2017: Drug Discovery Today
Madhu M Kanchi, Muthu K Shanmugam, Grishma Rane, Gautam Sethi, Alan P Kumar
Vitamin E family members: tocotrienols and tocopherols are widely known for their health benefits. Decades of research on tocotrienols have shown they have diverse biological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also modulate several intracellular molecular targets and, most importantly, have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials...
August 5, 2017: Drug Discovery Today
Maira Souza de Oliveira, Felipe Saldanha-Araujo, Alfredo Miranda de Goes, Fabricio F Costa, Juliana Lott de Carvalho
During the past decade, several types of stem cells have been investigated as promising therapeutic agents for cardiovascular diseases (CVDs). Among them, mesenchymal stem cells (MSCs) were the most investigated stem cell population. Hundreds of clinical trials later, results remain disappointing and far from the revolutionary improvements expected for heart function. In the present review, we address strategies under investigation to boost MSC therapy for CVDs. Pluripotent stem cells (PSCs) are also intended to reach clinical applications for CVDs, but here we suggest that, in the short term, the major impact of PSCs in the cardiovascular field might be at the bench and not the bedside...
August 4, 2017: Drug Discovery Today
Afrah J Abd, Rupinder K Kanwar, Jagat R Kanwar
AMD therapeutic strategies face several issues. Here, we review obstacles regarding considerations of successful therapy and offer suggested solutions.
August 3, 2017: Drug Discovery Today
Rutger H A Folmer
Since the importance of drug target residence time was first highlighted more 10 years ago, slow binding kinetics has received much attention in the drug discovery literature, and indeed within pharmaceutical research. However, the residence concept as presented in most papers is supported by rather misleading simulations and arguments, and by examples where compounds are taken out of their pharmacokinetic context. Moreover, fast association is typically more desirable than slow, and advantages of long residence time, notably a potential disconnect between pharmacodynamics (PD) and pharmacokinetics (PK), would be partially or completely offset by slow on-rate...
August 3, 2017: Drug Discovery Today
Kenneth A Jacobson, Dilip K Tosh, Kiran S Toti, Antonella Ciancetta
A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities...
August 3, 2017: Drug Discovery Today
Piotr Konieczny, Estela Selma-Soriano, Anna S Rapisarda, Juan M Fernandez-Costa, Manuel Perez-Alonso, Ruben Artero
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences...
August 2, 2017: Drug Discovery Today
Julia M Hillger, Wai-Ling Lieuw, Laura H Heitman, Adriaan P IJzerman
Drug development requires physiologically more appropriate model systems and assays to increase understanding of drug action and pathological processes in individual humans. Specifically, patient-derived cells offer great opportunities as representative cellular model systems. Moreover, with novel label-free cellular assays, it is often possible to investigate complex biological processes in their native environment. Combining these two offers distinct opportunities for increasing physiological relevance. Here, we review impedance-based label-free technologies in the context of patient samples, focusing on commonly used cell types, including fibroblasts, blood components, and stem cells...
August 1, 2017: Drug Discovery Today
Bin Zhou, Jesús Giraldo
G-protein-coupled receptors are central to signal transduction and cell communication. The possibility that cells use receptor heteromerization to modulate individual receptor pathways is a surmise that cannot be precluded. Given the complexity of these processes, mathematical models contribute to understanding how receptors and their respective ligands regulate signaling. Here, a mathematical model is presented that quantifies the allosteric interactions within a receptor heterodimer. The model is based on the operational model of allosterism including constitutive receptor activity, which provides the pharmacological analysis of heteromerization with well-established and widely used modeling and fitting procedures...
July 27, 2017: Drug Discovery Today
Nilesh M Meghani, Hardik H Amin, Beom-Jin Lee
The concept of click chemistry (CC), first introduced by K.B. Sharpless, has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), polymer chemistry, and material sciences. In this review, we outline novel aspects of CC related to drug discovery and drug delivery, with a brief overview of molecular mechanisms underlying each click reaction commonly used by researchers, and the main patents that paved the way for further diverse medicinal applications. We also describe recent progress in drug discovery and polymeric and carbon material-based drug delivery for potential pharmaceutical applications and advancements based on the CC approach, and discuss some intrinsic limitations of this popular conjugation reaction...
July 25, 2017: Drug Discovery Today
Robert Zeidler, Bruno Leonardo de Freitas Soares, Augustinus Bader, Shibashish Giri
Advanced chemotherapy fails to treat liver cancer but recent progress in understanding epigenetic modifications have witnessed promising clinical outcomes. Epigenetic alteration is the alteration of epigenomes (surrounding histone proteins) without changing the DNA sequence. Such epigenetic mechanisms include histone modifications such as methylation, acetylation, phosphorylation and sumoylation followed by changes in the genomic architecture. Current studies involving the understanding of small RNA molecules such as noncoding RNA and microRNA in modulating the chromatin architecture are explained in depth here, along with effects of some novel compounds from recent preclinical and clinical evidence...
July 25, 2017: Drug Discovery Today
Abraham Madariaga-Mazón, Andrés F Marmolejo-Valencia, Yangmei Li, Lawrence Toll, Richard A Houghten, Karina Martinez-Mayorga
Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression...
July 22, 2017: Drug Discovery Today
Jim Bosley, Christofer Boren, Sunjae Lee, Morten Grøtli, Jens Nielsen, Mathias Uhlen, Jan Boren, Adil Mardinoglu
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH...
July 20, 2017: Drug Discovery Today
Luong T H Nguyen, Aristo Muktabar, Jinkai Tang, Vinayak P Dravid, C Shad Thaxton, Subbu Venkatraman, Kee Woei Ng
Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. Nanotechnology has provided the possibility of designing nanoparticles that can translocate through tissues and home in to atherosclerotic plaques to achieve desired diagnostic, therapeutic, theranostic or 'theralivery' outcomes. Although nanomedicine approaches have demonstrated exciting possibilities, clinical reality is still distant and challenges are aplenty, such as specificity of targeting and nanotoxicity. Nevertheless, developments in formulations, delivery strategies and experimental models over the coming years will generate new knowledge to define the true potential of this field...
July 18, 2017: Drug Discovery Today
Meng Gao, Ben Zhong Tang
Conventional cancer therapy usually suffers from poor treatment efficiency and adverse effects. To improve the treatment efficiency, it is critical to precisely diagnose specific cancer types and monitor the therapy process in situ. Fluorescence imaging has the advantages of high sensitivity and easy operation, but conventional fluorophores suffer from aggregation-caused quenching (ACQ) and, therefore, their applications for imaging or diagnosis are severely impeded. By contrast, aggregation-induced emission (AIE) probes have significant advantages in terms of excellent photostability and a lack of self-quenching, and can be conveniently incorporated into theranostic platforms by combining them with various therapeutic modalities...
July 13, 2017: Drug Discovery Today
Chandana Mohanty, Sanjeeb K Sahoo
Oxidative damage and inflammation have been identified, through clinical and preclinical studies, as the main causes of nonhealing chronic wounds. Reduction of persistent chronic inflammation by application of antioxidant and anti-inflammatory agents such as curcumin has been well studied. However, low aqueous solubility, poor tissue absorption, rapid metabolism and short plasma half-life have made curcumin unsuitable for systemic administration for better wound healing. Recently, various topical formulations of curcumin such as films, fibers, emulsion, hydrogels and different nanoformulations have been developed for targeted delivery of curcumin at wounded sites...
July 12, 2017: Drug Discovery Today
Vishal B Siramshetty, Robert Preissner
A recent study demonstrated antifungal activity of dark chemical matter (DCM) compounds that were otherwise inactive in more than 100 HTS assays. These compounds were proposed to possess unique activity and 'clean' safety profiles. Here, we present an outlook of the promiscuity and safety of these compounds by retrospectively comparing their chemical and biological spaces with those of drugs. Significant amounts of marketed drugs (16%), withdrawn drugs (16.5%) and natural compounds (3.5%) share structural identity with DCM...
July 11, 2017: Drug Discovery Today
Prashant Kesharwani, Avinash Gothwal, Arun K Iyer, Keerti Jain, Manish K Chourasia, Umesh Gupta
Highly controllable dendritic structural design means dendrimers are a leading carrier in drug delivery applications. Dendrimer- and other nanocarrier-based hybrid systems are an emerging platform in the field of drug delivery. This review is a compilation of increasing reports of dendrimer interactions, such as dendrimer-liposome, dendrimer-carbon-nanotube, among others, known as hybrid carriers. This should prompt entirely new research with promising results for these hybrid carriers. It is assumed that such emerging hybrid nanosystems - from combining two already-established drug delivery platforms - could lead the way for the development of newer delivery systems with multiple applicability for latent theranostic applications in the future...
July 8, 2017: Drug Discovery Today
Esteban Orenes-Piñero, María A Esteve-Pastor, Mariano Valdés, Gregory Y H Lip, Francisco Marín
Intracardiac thrombus is a potentially life-threatening condition associated with atrial fibrillation (AF), with a high risk of embolic complications. Oral anticoagulation (OAC) therapy is the first-line treatment for its prevention or resolution. For many patients, traditional OAC treatment using vitamin K antagonists (VKAs; e.g., warfarin) is limited by several factors and the advent of non-VKA oral anticoagulants (NOACs), with improved efficacy and safety profiles, has provided additional treatment options...
July 7, 2017: Drug Discovery Today
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