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Drug Discovery Today

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https://www.readbyqxmd.com/read/28089787/antituberculosis-drugs-reducing-efflux-increasing-activity
#1
REVIEW
Liliana Rodrigues, Tanya Parish, Meenakshi Balganesh, José A Ainsa
In mycobacteria, it was assumed that efflux pumps only had a marginal role in drug resistance. In recent years, owing to the need to find novel drugs against multidrug-resistant tuberculosis, it has become clear that efflux should not be ignored. Although efflux inhibitors have been very useful for characterizing in vitro the properties of efflux pumps, their usefulness in vivo is limited because of their toxicity. Alternatively, programs aimed at discovering novel drugs for treating tuberculosis should implement strategies to characterize efflux liability of candidate drugs...
January 12, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28088443/quantifying-confidence-in-the-reporting-of-metabolic-biotransformations
#2
David J Ponting, Ernest Murray, Anthony Long
How confident can we be in the assignment of metabolite structures? Are the analytical techniques used sufficient to support hypotheses about what is being formed? In this Feature, we discuss the results of an extensive survey into the analytical techniques used, and their value in the characterisation of metabolites. The survey covers the structures of over 16 000 metabolites formed from 1732 query compounds, covering over 35 years of the literature and a variety of journals. The value of different characterisation techniques is considered, alongside or in the absence of synthetic standards...
January 11, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28088442/the-in-vivo-fate-of-nanocrystals
#3
REVIEW
Yi Lu, Jianping Qi, Xiaochun Dong, Weili Zhao, Wei Wu
There has been significant research interest in, and development of, nanocrystals in recent years for the delivery of poorly water-soluble drugs via various routes. However, there is a common misinterpretation of nanocrystallization as an approach to modulate, and more specifically to enhance, the dissolution of drug crystals. Nevertheless, it is possible for nanocrystals to interact with biological tissues because nanocrystals can survive for a longer duration in vivo compared with solution counterparts. Therefore, understanding the in vivo fate of nanocrystals and determining its contribution to efficacy is of tremendous significance for optimizing the performance of nanocrystals...
January 11, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28017837/in-vitro-and-in-vivo-evaluation-of-in-situ-gelling-systems-for-sustained-topical-ophthalmic-delivery-state-of-the-art-and-beyond
#4
REVIEW
Pierre-Louis Destruel, Ni Zeng, Marc Maury, Nathalie Mignet, Vincent Boudy
In situ gelling delivery systems for the ocular administration of drugs has been a major focus of research over the past two decades, improving the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration. This drug delivery strategy results in high ocular bioavailability by avoiding rapid precorneal clearance resulting from nasolacrimal drainage and eye blinking. However, the development of such unconventional forms requires many parameters to be mastered, such as gelation time, viscoelastic behavior, mucoadhesion, and sustained release...
December 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/28017836/recent-advances-in-hyaluronic-acid-decorated-nanocarriers-for-targeted-cancer-therapy
#5
REVIEW
Jennifer M Wickens, Hashem O Alsaab, Prashant Kesharwani, Ketki Bhise, Mohd Cairul Iqbal Mohd Amin, Rakesh Kumar Tekade, Umesh Gupta, Arun K Iyer
The cluster-determinant 44 (CD44) receptor has a high affinity for hyaluronic acid (HA) binding and is a desirable receptor for active targeting based on its overexpression in cancer cells compared with normal body cells. The nanocarrier affinity can be increased by conjugating drug-loaded carriers with HA, allowing enhanced cancer cell uptake via the HA-CD44 receptor-mediated endocytosis pathway. In this review, we discuss recent advances in HA-based nanocarriers and micelles for cancer therapy. In vitro and in vivo experiments have repeatedly indicated HA-based nanocarriers to be a target-specific drug and gene delivery platform with great promise for future applications in clinical cancer therapy...
December 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27993550/are-sar-tables-obsolete
#6
EDITORIAL
Celerino Abad-Zapatero
No abstract text is available yet for this article.
December 16, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27988358/feature-selection-in-clinical-proteomics-with-great-power-comes-great-reproducibility
#7
REVIEW
Wei Wang, Andrew C-H Sue, Wilson W B Goh
In clinical proteomics, reproducible feature selection is unattainable given the standard statistical hypothesis-testing framework. This leads to irreproducible signatures with no diagnostic power. Instability stems from high P-value variability (p_var), which is inevitable and insolvable. The impact of p_var can be reduced via power increment, for example increasing sample size and measurement accuracy. However, these are not realistic solutions in practice. Instead, workarounds using existing data such as signal boosting transformation techniques and network-based statistical testing is more practical...
December 15, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27988360/targeted-delivery-for-regenerative-medicines-an-untapped-opportunity-for-drug-conjugates
#8
Eric Valeur, Laurent Knerr, Maria Ölwegård-Halvarsson, Malin Lemurell
Regenerative approaches are promising avenues to effectively cure diseases rather than merely treating symptoms, but are associated with concerns around proliferation in other organs. Given that targeted delivery holds the promise of delivering a drug precisely to its desired site of action, usually with the prospect of increasing the therapeutic index, it can be considered as an essential enabler of regenerative medicines. Although significant progress has been made predominantly in oncology for the delivery of cytotoxic drugs using antibody-drug conjugates (ADCs), the physiological conditions and safety requirements for regenerative medicines are very different...
December 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27988359/targeting-amino-acid-metabolism-for-cancer-therapy
#9
REVIEW
Michael J Lukey, William P Katt, Richard A Cerione
To support sustained biomass accumulation, tumor cells undergo metabolic reprogramming. Nutrient transporters and metabolic enzymes are regulated by the same oncogenic signals that drive cell-cycle progression. Some of the earliest cancer therapies used antimetabolites to disrupt tumor metabolism, and there is now renewed interest in developing drugs that target metabolic dependencies. Many cancers exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis...
December 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27988357/recombinant-alpha-1-microglobulin-a-potential-treatment-for-preeclampsia
#10
REVIEW
Rolf Gunnarsson, Bo Åkerström, Stefan R Hansson, Magnus Gram
Preeclampsia is a serious pregnancy-specific condition, affecting 10 million women annually worldwide. No specific treatment is currently available. Recent studies have demonstrated abnormal production and accumulation of free fetal hemoglobin in the preeclamptic placenta, and identified subsequent leakage into the maternal circulation as an important factor in the development of preeclampsia. A recombinant version of alpha-1-microglobulin, an endogenous well-characterized heme and radical scavenger, has been developed...
December 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27979712/simultaneous-screening-and-detection-of-pharmaceutical-co-crystals-by-the-one-step-dsc-ftir-microspectroscopic-technique
#11
REVIEW
Shan-Yang Lin
Various methods and analytical techniques for the preparation and identification of pharmaceutical co-crystals have been applied, but these operations require considerable time for the screening and preparation of co-crystals. In this review, a powerful method that combines Fourier-transform infrared (FTIR) microspectroscopy with thermal analysis is introduced. This unique one-step real-time differential scanning calorimetry (DSC)-FTIR microspectroscopic approach has been successfully applied to simultaneously and directly screen and detect pharmaceutical co-crystal formation in systems such as indomethacin-saccharin, indomethacin-nicotinamide, carbamazepine-glutaric-acid, metaxalone-succinic-acid and piroxicam-saccharin...
December 12, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27965161/molecular-similarity-considerations-in-the-licensing-of-orphan-drugs
#12
REVIEW
Pedro Franco, Nuria Porta, John D Holliday, Peter Willett
The large costs associated with modern drug discovery mean that governments and regulatory bodies need to provide economic incentives to promote the development of orphan drugs (i.e., medicinal products that are designed to treat rare disease that affect only small numbers of patients). Under European Union (EU) legislation, a medicine can only be authorised for treating a specific rare disease if it is not similar to other orphan drugs already authorised for that particular disease. Here, we discuss the use of 2D fingerprints to calculate the Tanimoto similarity between potential and existing orphan drugs for the same disease, and present logistic regression models correlating these computed similarities with the judgements of human experts...
December 10, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27956056/chemokine-neutralization-as-an-innovative-therapeutic-strategy-for-atopic-dermatitis
#13
REVIEW
Dayana Abboud, Julien Hanson
Atopic dermatitis is a chronic inflammatory skin disease with no specific treatment, affecting 15-30% of children and 2-10% of adults in developed countries. Current therapies alleviate symptoms and include emollients, glucocorticoids and calcineurin inhibitors. The limited efficiency and side-effects of these medicines call for better treatment, and a cure for atopic dermatitis represents an unmet medical need. The chemokine/chemokine-receptor network constitutes an attractive target for drugs in atopic dermatitis...
December 9, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27939283/global-vision-of-druggability-issues-applications-and-perspectives
#14
REVIEW
Hiba Abi Hussein, Colette Geneix, Michel Petitjean, Alexandre Borrel, Delphine Flatters, Anne-Claude Camproux
During the preliminary stage of a drug discovery project, the lack of druggability information and poor target selection are the main causes of frequent failures. Elaborating on accurate computational druggability prediction methods is a requirement for prioritizing target selection, designing new drugs and avoiding side effects. In this review, we describe a survey of recently reported druggability prediction methods mainly based on networks, statistical pocket druggability predictions and virtual screening...
December 6, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27919806/are-placebo-and-drug-specific-effects-additive-questioning-basic-assumptions-of-double-blinded-randomized-clinical-trials-and-presenting-novel-study-designs
#15
REVIEW
Tobias Kube, Winfried Rief
Double-blinded randomized clinical trials (RCTs) assume that pharmacological interventions have drug-specific and unspecific components. Traditional RCTs postulate an additivity of these two components. In this review, we provide evidence from both clinical trials and experimental studies that questions this 'additive model'. Given that the evaluation of drug treatments in RCTs is based on the assumption of additivity, its violation has far-reaching consequences. Therefore, we discuss an interactive model that, in contrast to the additive model, considers interactions between placebo and drug-specific effects...
December 2, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27919805/uplc-ms-for-metabolomics-a-giant-step-forward-in-support-of-pharmaceutical-research
#16
REVIEW
Ala F Nassar, Terence Wu, Samuel F Nassar, Adam V Wisnewski
Metabolomics is a relatively new and rapidly growing area of post-genomic biological research. As use of metabolomics technology grows throughout the spectrum of drug discovery and development, and its applications broaden, its impact is expanding dramatically. This review seeks to provide the reader with a brief history of the development of metabolomics, its significance and strategies for conducting metabolomics studies. The most widely used analytical tools for metabolomics: NMR, LC-MS and GC-MS, are discussed along with considerations for their use...
December 2, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27916639/binding-thermodynamics-discriminates-fragments-from-druglike-compounds-a-thermodynamic-description-of-fragment-based-drug-discovery
#17
REVIEW
Glyn Williams, György G Ferenczy, Johan Ulander, György M Keserű
Small is beautiful - reducing the size and complexity of chemical starting points for drug design allows better sampling of chemical space, reveals the most energetically important interactions within protein-binding sites and can lead to improvements in the physicochemical properties of the final drug. The impact of fragment-based drug discovery (FBDD) on recent drug discovery projects and our improved knowledge of the structural and thermodynamic details of ligand binding has prompted us to explore the relationships between ligand-binding thermodynamics and FBDD...
December 1, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27903430/minimizing-the-risk-of-chemically-reactive-metabolite-formation-of-new-drug-candidates-implications-for-preclinical-drug-design
#18
Andreas Brink, Axel Pähler, Christoph Funk, Franz Schuler, Simone Schadt
Many pharmaceutical companies aim to reduce reactive metabolite formation by chemical modification at early stages of drug discovery. A practice often applied is the detection of stable trapping products of electrophilic intermediates with nucleophilic trapping reagents to guide rational structure-based drug design. This contribution delineates this strategy to minimize the potential for reactive metabolite formation of clinical candidates during preclinical drug optimization, exemplified by the experience at Roche over the past decade...
November 27, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27894931/the-unique-status-of-first-in-human-studies-strengthening-the-social-value-requirement
#19
Michelle G J L Habets, Johannes J M van Delden, Annelien L Bredenoord
For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials...
November 25, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890821/molecular-dynamics-driven-drug-discovery-leaping-forward-with-confidence
#20
REVIEW
Aravindhan Ganesan, Michelle L Coote, Khaled Barakat
Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery...
November 25, 2016: Drug Discovery Today
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