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Expert Opinion on Drug Discovery

Carlos F M Silva, Diana C G A Pinto, Artur M S Silva
Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for the great majority of age-related dementias affecting daily life through memory loss and cognitive impairment. From a molecular point of view, the most common neuropathological characteristics found in AD patients are abnormal protein deposits, particularly senile plaques (SP) and neurofibrillary tangles (NFT). Furthermore, the currently available pharmacological treatment only provides short-term improvements and is focused on the use of cholinesterase (ChEs) inhibitors or memantine, an approved medicine that is a glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker...
November 15, 2018: Expert Opinion on Drug Discovery
Aishwarya Satpathy, Pallab Datta, Yang Wu, Bugra Ayan, Ertugrul Bayram, Ibrahim T Ozbolat
Although there have been significant contributions from the pharmaceutical industry to clinical practice, several diseases remain unconquered, with the discovery of new drugs remaining a paramount objective. The actual process of drug discovery involves many steps including pre-clinical and clinical testing, which are highly time- and resource-consuming, driving researchers to improve the process efficiency. The shift of modelling technology from two-dimensions (2D) to three-dimensions (3D) is one of such advancements...
November 1, 2018: Expert Opinion on Drug Discovery
Pathan Mohsin Khan, Kunal Roy
Quantitative structure-activity/property relationships (QSAR/QSPR) are statistical models which quantitatively correlate quantitative chemical structure information (described as molecular descriptors) to the response endpoints (biological activity, property, toxicity etc.). Important strategies for QSAR model development and validation include dataset curation, variable selection, and dataset division, selection of modeling algorithms and appropriate measures of model validation. Areas covered: Different feature selection methods and various linear and nonlinear learning algorithms are employed to address the complexity of data sets for selection of appropriate features important for the responses being modeled, to reduce over fitting of the models, and to derive interpretable models...
October 29, 2018: Expert Opinion on Drug Discovery
Edin J Mifsud, Celeste Mk Tai, Aeron C Hurt
Influenza continues to be a major public health concern. Antivirals play an important role in limiting the burden of disease and preventing infection and/or transmission. The developments of such agents are heavily dependent on pre-clinical evaluation where animal models are used to answer questions that cannot be easily addressed in human clinical trials. There are numerous animal models available to study the potential benefits of influenza antivirals but each animal model has its own pros and cons. Areas covered: In this review, the authors describe the advantages and disadvantages of using mice, ferrets, guinea pigs, cotton rats, golden hamsters and non-human primates to evaluate influenza therapeutics...
October 26, 2018: Expert Opinion on Drug Discovery
Alan O Trounson, Andrew J French
No abstract text is available yet for this article.
October 25, 2018: Expert Opinion on Drug Discovery
Henriette Holst Nerild, Mikkel Bring Christensen, Filip Krag Knop, Andreas Brønden
Type 2 diabetes (T2D) is a major global health challenge associated with increased cardiovascular morbidity and mortality. Intervention strategies managing multiple risk factors (hyperglycemia, hypertension and dyslipidemia) in patients with T2D can reduce the risk of cardiovascular disease by ~50%. Areas covered: Herein, the authors provide an update on the development and clinical potential of colesevelam as a glucose-lowering drug in T2D. Furthermore, they outline the pharmacokinetics, pharmacodynamics, and the clinical efficacy and safety data from the studies carried out to obtain market authorization for colesevelam...
October 19, 2018: Expert Opinion on Drug Discovery
Verena Schöning, Felix Hammann
No abstract text is available yet for this article.
October 18, 2018: Expert Opinion on Drug Discovery
Paul W Denny
Both in vitro biochemical and phenotypic assay platforms have clear limitations in high throughput screening (HTS) for drug discovery. The use of genetically tractable model yeast as a vehicle for target-based HTS overcomes many of these by allowing the identification of on-target compounds that function within a eukaryotic cellular context. Areas covered: In this special report, the use of yeast-based assays in HTS is discussed with reference to the various platforms that have been utilized over the past 20 years...
October 16, 2018: Expert Opinion on Drug Discovery
Christos Iliopoulos-Tsoutsouvas, Rohit N Kulkarni, Alexandros Makriyannis, Spyros P Nikas
G-protein-coupled receptors (GPCRs) mediate the effects of approximately 33% of all marketed drugs. The development of tools to study GPCR pharmacology is urgently needed as it can lead to the discovery of safer and more effective medications. Fluorescent GPCR ligands represent highly sensitive and safe small-molecule tools for real-time exploration of the life of the receptor, cellular signaling, and ligand-/receptor-receptor interactions in cellulo and/or in vivo. Areas covered: This review summarizes relevant information from published literature and provides critical insights into the design of successful small-molecule fluorescent probes for Class A GPCRs as potential major targets for drug development...
September 24, 2018: Expert Opinion on Drug Discovery
Bence Szilágyi, György G Ferenczy, György M Keserű
D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia. Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility...
September 17, 2018: Expert Opinion on Drug Discovery
Heitor G Araújo-Filho, Erik W M Pereira, Adriana Rolim Campos, Lucindo J Quintans-Júnior, Jullyana S S Quintans
Chronic orofacial pain is one of the most common pain conditions experienced by adults. Animal models are often selected as the most useful scientific methodology to explore the pathophysiology of the disorders that cause this disabling pain to facilitate the development of new treatments. The creation of new models or the improvement of existing ones is essential for finding new ways to approach the complex neurobiology of this type of pain. Areas covered: The authors describe and discuss a variety of animal models used in chronic orofacial pain (COFP)...
September 17, 2018: Expert Opinion on Drug Discovery
Fisayo Olotu, Emmanuel Adeniji, Clement Agoni, Imane Bjij, Shama Khan, Ahmed Elrashedy, Mahmoud Soliman
Over the years, not a single HSP inhibitor has progressed into the post-market phase of drug development despite the success recorded in various pre-clinical and clinical studies. The inability of existing drugs to specifically target oncogenic HSPs has majorly accounted for these setbacks. Recent combinatorial strategies that incorporated computer-aided drug design (CADD) techniques are geared towards the development of highly specific HSP inhibitors with increased activities and minimal toxicities. Areas covered: In this review, strategic therapeutic approaches that have recently aided the development of selective HSP inhibitors were highlighted...
September 12, 2018: Expert Opinion on Drug Discovery
Paula Blanco, Fernando Sanz-García, Sara Hernando-Amado, José Luis Martínez, Manuel Alcalde-Rico
One of the possibilities for reducing the emergence and spread of antibiotic resistance is the use of anti-resistance compounds capable of resensitizing resistant microorganisms to current antimicrobials. For this purpose, multidrug efflux pumps, whose inhibition may increase bacterial susceptibility to several antibiotics, including macrolides to which Gram-negatives are considered intrinsically resistant, have emerged as suitable targets. Areas covered: In the current review, the authors discuss different mechanisms that can be exploited for inhibiting multidrug efflux pumps and describe the properties and the potential therapeutic value of already studied efflux pumps inhibitors...
September 10, 2018: Expert Opinion on Drug Discovery
Joseph V Pergolizzi, Jo Ann LeQuang, Robert Taylor, Michael H Ossipov, Daniel Colucci, Robert B Raffa
The recent dramatic increase in intentional and unintentional deaths attributed to opioids has refocused attention on the therapeutic ratio (risk-benefit ratio) of opioid analgesics. Almost all traditional opioid analgesics produce their effects (therapeutic and adverse) via the activation of μ-opioid receptor (MOR) pathways. It is therefore important to examine the question of whether this natural endogenous pathway can still be activated, but with greater safety. Areas covered: Other comprehensive reviews have focused on pharmacokinetic (e...
September 3, 2018: Expert Opinion on Drug Discovery
Mathew Renwick, Elias Mossialos
No abstract text is available yet for this article.
September 1, 2018: Expert Opinion on Drug Discovery
Ashok Vaidya, Anuradha Roy, Rathnam Chaguturu
No abstract text is available yet for this article.
August 27, 2018: Expert Opinion on Drug Discovery
Ewout J N Groen
No abstract text is available yet for this article.
August 27, 2018: Expert Opinion on Drug Discovery
Apurba Bhattarai, Yinglong Miao
Understanding pathways and mechanisms of drug binding to receptors is important for rational drug design. Remarkable advances in supercomputing and methodological developments have opened a new era for application of computer simulations in predicting drug-receptor interactions at an atomistic level. Gaussian accelerated molecular dynamics (GaMD) is a computational enhanced sampling technique that works by adding a harmonic boost potential to reduce energy barriers. GaMD enables free energy calculations without the requirement of predefined collective variables...
November 2018: Expert Opinion on Drug Discovery
Miles Congreve, Giles A Brown, Alexandra Borodovsky, Michelle L Lamb
Adenosine A2A Receptor (A2A R) antagonists are an emerging class of agents that treat cancers, both as a monotherapy and in combination with other therapeutic agents. Several studies support the accumulation of extracellular adenosine in the tumor microenvironment as a critical mechanism in immune evasion implicating A2A R antagonists for use in immuno-oncology. Areas covered: In this perspective article, the authors briefly outline the history of the A2A R antagonist field for central nervous system indications and give their perspective on the status of agents progressing today in oncology...
November 2018: Expert Opinion on Drug Discovery
Russell Costello, Adrien Kissenpfennig, Paulo N Martins, James McDaid
The development of all immunosuppressant agents to date has involved the experimental use of large and small animal models. Over the last half-century, immunosuppressive drugs have extended the lives of transplant patients worldwide. However, the use of animal models in the development of these drugs is not perfect, and this has brought to light a number of issues including idiosyncratic reactions that are found in animal models but not in humans. The 2006 highly publicized case of the 'elephant man' TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models...
November 2018: Expert Opinion on Drug Discovery
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