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Expert Opinion on Drug Discovery

W J van den Brink, T Hankemeier, P H van der Graaf, E C M de Lange
Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man...
March 8, 2018: Expert Opinion on Drug Discovery
David J Newman
No abstract text is available yet for this article.
March 7, 2018: Expert Opinion on Drug Discovery
Khalid Iqbal, Fei Liu, Cheng-Xin Gong
Alzheimer's disease (AD), which accounts for three fourth of all cases of dementia, is a major public health problem in modern society and, yet, there is no effective treatment available that can prevent or inhibit this chronic progressive neurodegenerative disease. A major current drug target is intraneuronal abnormally hyperphosphorylated microtubule-associated protein tau which is a histopathological hallmark of this disease and of a family of neurodegenerative diseases called tauopathies. Areas covered: In this review, the authors discuss a growing number of studies that describe the nature and mechanism of tau pathology and various drug discovery options and most recent developments in tau-based therapeutics...
March 1, 2018: Expert Opinion on Drug Discovery
Claudia Volpi, Francesca Fallarino, Giada Mondanelli, Antonio Macchiarulo, Ursula Grohmann
Until recently, metabotropic glutamate receptor 4 (mGlu4) has not received adequate attention in terms of drug targeting when compared to other members of the same mGlu receptor family, possibly because of the difficulties encountered in developing highly selective, either orthosteric or allosteric, ligands for this receptor. Areas covered: This review gives to discussion to the past and recent advances (between 2012-2017) in targeting the mGlu4 receptor for the treatment of disorders of the central nervous system (CNS) as well as immunological (neuroinflammation) and metabolic diseases (diabetes)...
February 28, 2018: Expert Opinion on Drug Discovery
Bert A 't Hart, Jon D Laman, Yolanda S Kap
The translation of scientific discoveries made in animal models into effective treatments for patients often fails, indicating that currently used disease models in preclinical research are insufficiently predictive for clinical success. An often-used model in the preclinical research of autoimmune neurological diseases, multiple sclerosis in particular, is experimental autoimmune encephalomyelitis (EAE). Most EAE models are based on genetically susceptible inbred/SPF mouse strains used at adolescent age (10-12 weeks), which lack exposure to genetic and microbial factors which shape the human immune system...
February 21, 2018: Expert Opinion on Drug Discovery
Juliet E Wolford, Krishnansu S Tewari
Though cervical cytology, HPV DNA testing, and pre-invasive disease management has significantly reduced the number new diagnoses of cervical cancer, women with persistent oncogenic HPV variants are at significant risk for developing invasive cervical cancer. Early stage and locally advanced disease can be cured, but women with advanced or recurrent disease have a very poor prognosis. This underscores the need for different treatment paradigms for advanced cervical cancer, the most promising of which are novel therapeutics that target the ability of HPV to overcome host immune tolerance...
February 21, 2018: Expert Opinion on Drug Discovery
Michał Kiełbus, Jakub Czapiński, Adrian Odrzywolski, Grażyna Stasiak, Kamila Szymańska, Joanna Kałafut, Michał Kos, Krzysztof Giannopoulos, Andrzej Stepulak, Adolfo Rivero-Müller
The discovery and domestication of biomolecules that respond to light has taken a light of its own, providing new molecular tools with incredible spatio-temporal resolution to manipulate cellular behavior. Areas covered: The authors herein analyze the current optogenetic tools in light of their current, and potential, uses in cancer drug discovery, biosafety and cancer biology. Expert opinion: The pipeline from drug discovery to the clinic is plagued with drawbacks, where most drugs fail in either efficacy or safety...
February 15, 2018: Expert Opinion on Drug Discovery
JungIn Um, Ji-Hyung Lee, Da-Woon Jung, Darren R Williams
Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells...
February 8, 2018: Expert Opinion on Drug Discovery
Luca Mazzarella, Giuseppe Curigliano
There is a pressing need to improve strategies to select candidate drugs early on in the drug development pipeline, especially in oncology, as the efficiency of new drug approval has steadily declined these past years. Traditional methods of drug screening have relied on low-cost assays on cancer cell lines growing on plastic dishes. Recent massive-scale screens have generated big data amenable for sophisticated computational modeling and integration with clinical data. However, 2D culturing has several intrinsic limitations and novel methodologies have been devised for culturing in three dimensions, to include cells from the tumor immune microenvironment...
February 7, 2018: Expert Opinion on Drug Discovery
Emanuela Corsini, Manuela Casula, Elena Tragni, Valentina Galbiati, Marc Pallardy
Drug hypersensitivity reactions (DHRs) are common adverse effects of pharmaceuticals that clinically resemble allergies, and which are becoming an important burden to healthcare systems. Alongside accurate diagnostic techniques, tools which can predict potential drug-inducing hypersensitivity reactions in the pre-clinical phase are critical. Despite the important adverse reactions linked to immune-mediated hypersensitivity, at present, there are no validated or required in vivo or in vitro methods to screen the sensitizing potential of drugs and their metabolites in the pre-clinical phase...
February 6, 2018: Expert Opinion on Drug Discovery
Yijun Huang
Therapeutic modulation of complement activation is considered as a promising approach for the treatment of host tissue damage in several inflammatory and autoimmune diseases. Complement component protein C3 is a particularly attractive drug target for complement inhibitors, due to its central role in three pathways of complement activation cascade. Areas covered: The author provides a comprehensive review on compstatin family peptides which have been discovered and optimized as potent and selective C3 inhibitors via a combination of chemical, biophysical and computational approaches...
February 5, 2018: Expert Opinion on Drug Discovery
Hisham Qosa, Donna A Volpe
Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases. Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed...
February 2, 2018: Expert Opinion on Drug Discovery
Aditi P Singh, Diego Adrianzen Herrera, Yifei Zhang, Roman Perez-Soler, Haiying Cheng
Squamous cell lung cancer (SQCLC) is the second most common subtype of non-small cell lung cancer (NSCLC) and has limited therapeutic options. Its development is likely a result of a multistep process in response to chronic tobacco exposure, involving sequential metaplasia, dysplasia and invasive carcinoma. Its complex genomic landscape has recently been revealed but no driver mutations have been validated that could lead to molecularly targeted therapy as have emerged in lung adenocarcinoma. Few preclinical murine models exist for testing and developing novel therapeutics in SQCLC...
February 2, 2018: Expert Opinion on Drug Discovery
Goldis Malek, Julia Busik, Maria B Grant, Mayur Choudhary
The impact of vision debilitating diseases is a global public health concern, which will continue until effective preventative and management protocols are developed. Two retinal diseases responsible for the majority of vision loss in the working age adults and elderly populations are diabetic retinopathy (DR) and age-related macular degeneration (AMD), respectively. Model systems, which recapitulate aspects of human pathology, are valid experimental modalities that have contributed to the identification of signaling pathways involved in disease development and consequently potential therapies...
January 30, 2018: Expert Opinion on Drug Discovery
Mireia Rosell, Juan Fernández-Recio
Protein-protein interactions are important for biological processes and pathological situations, and are attractive targets for drug discovery. However, rational drug design targeting protein-protein interactions is still highly challenging. Hot-spot residues are seen as the best option to target such interactions, but their identification requires detailed structural and energetic characterization, which is only available for a tiny fraction of protein interactions. Areas covered: In this review, the authors cover a variety of computational methods that have been reported for the energetic analysis of protein-protein interfaces in search of hot-spots, and the structural modeling of protein-protein complexes by docking...
January 29, 2018: Expert Opinion on Drug Discovery
Ines Trigo-Damas, Natalia Lopez-Gonzalez Del Rey, Javier Blesa
Parkinson's disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson's Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times. Areas covered: The authors provide an outline of the various traditional models of Parkinson´s disease and address those that have been recently generated...
January 24, 2018: Expert Opinion on Drug Discovery
Ivana Cacciatore, Michele Ciulla, Lisa Marinelli, Piera Eusepi, Antonio Di Stefano
Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension. Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system...
January 23, 2018: Expert Opinion on Drug Discovery
Michele Fornaro, Lubna Kardash, Stefano Novello, Andrea Fusco, Annalisa Anastasia, Domenico De Berardis, Giampaolo Perna, Mauro Giovanni Carta
Bipolar disorder (BD) is a considerable burden to the affected individual. The need for novel drug targets and improved drug design (DD) in BD is therefore clear. Areas covered: The following article provides a brief, narrative, clinician-oriented overview of the most promising novel pharmacological targets for BD along with a concise overview regarding the general DD process and the unmet needs relevant to BD. Expert opinion: A number of novel potential drug targets have been investigated. With the notable exception of the kynurenine pathway, available evidence is too scarce to highlight a definitive roadmap for forthcoming DD in BD...
January 22, 2018: Expert Opinion on Drug Discovery
Alison Obergrussberger, Tom A Goetze, Nina Brinkwirth, Nadine Becker, Søren Friis, Markus Rapedius, Claudia Haarmann, Ilka Rinke-Weiß, Sonja Stölzle-Feix, Andrea Brüggemann, Michael George, Niels Fertig
Automated patch clamp (APC) devices have become commonplace in many industrial and academic labs. Their ease-of-use and flexibility have ensured that users can perform routine screening experiments and complex kinetic experiments on the same device without the need for months of training and experience. APC devices are being developed to increase throughput and flexibility. Areas covered: Experimental options such as temperature control, internal solution exchange and current clamp have been available on some APC devices for some time, and are being introduced on other devices...
January 17, 2018: Expert Opinion on Drug Discovery
Elizabeth Magnotti, Wayne A Marasco
Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer...
January 17, 2018: Expert Opinion on Drug Discovery
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