Showing papers in "Expert Opinion on Drug Discovery in 2015"
TL;DR: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications.
Abstract: Introduction: The molecular mechanics energies combined with the Poisson–Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor–ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success.Areas covered: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications.Expert opinion: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used success...
2,480 citations
TL;DR: The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging.
Abstract: Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer’s disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals.Areas covered: This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging.Expert opinion: Animal models...
164 citations
TL;DR: This article reviews the developments of MCMs to combat ARS, with particular reference to the various animal models utilized for the in-depth evaluation, and the objective, pathways and challenges of the FDA Animal Efficacy Rule are discussed.
Abstract: Introduction: Although significant scientific advances have been made over the past six decades in developing safe, nontoxic and effective radiation/medical countermeasures (MCMs) for acute radiation syndrome (ARS), no drug has been approved by the US FDA. The availability of adequate animal models is a prime requisite under the criteria established by the FDA ‘animal rule’ for the development of novel MCMs for ARS and the discovery of biomarkers for radiation exposure.Areas covered: This article reviews the developments of MCMs to combat ARS, with particular reference to the various animal models (rodents: mouse and rat; canine: beagle; minipigs and nonhuman primates [NHPs]) utilized for the in-depth evaluation. The objective, pathways and challenges of the FDA Animal Efficacy Rule are also discussed.Expert opinion: There are a number of well-defined animal models, the mouse, canine and NHP, that are being used for the development of MCMs. Additional animal models, such as the minipig, are under developm...
106 citations
TL;DR: This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, that is, RhoA, Rac1, and Cdc42, that are key regulators and effectors in cancer.
Abstract: Introduction: Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression, and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure–function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells.Areas covered: This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, that is, RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approac...
102 citations
TL;DR: This paper presents an overview of conformational sampling methods treating target flexibility during molecular docking, using classical biomolecular recognition models to classify existing docking methods.
Abstract: Introduction: Protein–ligand interactions play key roles in various metabolic pathways, and the proteins involved in these interactions represent major targets for drug discovery. Molecular docking is widely used to predict the structure of protein–ligand complexes, and protein flexibility stands out as one of the most important and challenging issues for binding mode prediction. Various docking methods accounting for protein flexibility have been proposed, tackling problems of ever-increasing dimensionality.Areas covered: This paper presents an overview of conformational sampling methods treating target flexibility during molecular docking. Special attention is given to approaches considering full protein flexibility. Contrary to what is frequently done, this review does not rely on classical biomolecular recognition models to classify existing docking methods. Instead, it applies algorithmic considerations, focusing on the level of flexibility accounted for. This review also discusses the diversity of d...
97 citations
TL;DR: A widespread application of this methodology is predicted in different medical technological areas, including biosensing, monitoring, molecular imaging, gene therapy, vaccine development and nanotechnology.
Abstract: Introduction: Over the past decade, several library-based methods have been developed to discover ligands with strong binding affinities for their targets. These methods mimic the natural evolution for screening and identifying ligand–target interactions with specific functional properties. Phage display technology is a well-established method that has been applied to many technological challenges including novel drug discovery.Areas covered: This review describes the recent advances in the use of phage display technology for discovering novel bioactive compounds. Furthermore, it discusses the application of this technology to produce proteins and peptides as well as minimize the use of antibodies, such as antigen-binding fragment, single-chain fragment variable or single-domain antibody fragments like VHHs.Expert opinion: Advances in screening, manufacturing and humanization technologies demonstrate that phage display derived products can play a significant role in the diagnosis and treatment of disease....
92 citations
TL;DR: The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness, and drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF.
Abstract: Introduction: Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts.Areas covered: In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8+NK group 2D-positive (NKG2D+) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy.Expert opinion: The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of e...
90 citations
TL;DR: The aim of this review is to show how QSAR modeling can be applied in novel drug discovery, design and lead optimization in the absence of 3D structures of specific drug targets.
Abstract: Introduction: Quantitative structure–activity relationship (QSAR) modeling is one of the most popular computer-aided tools employed in medicinal chemistry for drug discovery and lead optimization. It is especially powerful in the absence of 3D structures of specific drug targets. QSAR methods have been shown to draw public attention since they were first introduced.Areas covered: In this review, the authors provide a brief discussion of the basic principles of QSAR, model development and model validation. They also highlight the current applications of QSAR in different fields, particularly in virtual screening, rational drug design and multi-target QSAR. Finally, in view of recent controversies, the authors detail the challenges faced by QSAR modeling and the relevant solutions. The aim of this review is to show how QSAR modeling can be applied in novel drug discovery, design and lead optimization.Expert opinion: QSAR should intentionally be used as a powerful tool for fragment-based drug design platform...
90 citations
TL;DR: Tissue models are just emerging as a new tool for cancer drug discovery, they are already demonstrating potential for recapitulating, in vitro, the native behavior of human tumors, but numerous challenges need to be addressed before they can have platforms with a predictive power appropriate for the pharmaceutical industry.
Abstract: Introduction: Drug toxicity often goes undetected until clinical trials, which are the most costly and dangerous phase of drug development. Both the cultures of human cells and animal studies have limitations that cannot be overcome by incremental improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. An area that could greatly benefit from these models is cancer research.Areas covered: In this review, the authors first describe the engineered tumor systems, using Ewing’s sarcoma as an example of human tumor that cannot be predictably studied in cell culture and animal models. Then, they discuss the importance of the tissue context for cancer progression and outline the biomimetic principles for engineering human tumors. Finally, they discuss the utility of bioengineered tumor mo...
78 citations
TL;DR: This review gives a brief general overview of in vitro and in vivo BBB models used in the pre-clinical evaluation of CNS-targeting drugs, with particular focus on the recent progress in developing humanized models.
Abstract: Introduction: The majority of therapeutics, small molecule or biologics, developed for the CNS do not penetrate the blood–brain barrier (BBB) sufficiently to induce pharmacologically meaningful effects on CNS targets. To improve the efficiency of CNS drug discovery, several in vitro models of the BBB have been used to aid early selection of molecules with CNS exposure potential. However, correlative studies suggest relatively poor predictability of in vitro BBB models underscoring the need to combine in vitro and in vivo BBB penetration assessment into an integrated preclinical workflow.Areas covered: This review gives a brief general overview of in vitro and in vivo BBB models used in the pre-clinical evaluation of CNS-targeting drugs, with particular focus on the recent progress in developing humanized models. The authors discuss the advantages, limitations, in vitro–in vivo correlation, and integration of these models into CNS drug discovery and development with the aim of improving translation.Expert ...
69 citations
TL;DR: The application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery and several pathways and pharmacological targets in the central nervous system that play an important role in the regulation of feeding behavior and energy homeostasis are described.
Abstract: Introduction: Obesity is a body weight disorder characterized by excess adiposity that increases the risk for developing co-morbidities such as type 2 diabetes. A large medical need exists for new anti-obesity treatments capable of promoting 10% or greater weight loss, with minimal side effects.Areas covered: The authors describe the application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery. Furthermore, they review in detail several pathways and pharmacological targets in the central nervous system (e.g., the leptin-melanocortin axis, the opioid system, GLP-1/GLP-1 system, and FGF21/FGFR1c/β-Klotho axis) that play an important role in the regulation of feeding behavior and energy homeostasis. Special focus is given to new strategies that engage well-known targets via novel mechanisms in order to circumvent issues seen with previous drug candidates that failed in the clinic. Finally, the authors discuss the recent developments arou...
TL;DR: ADCs are at the beginning of the next stage in their evolution and as these newer formats are developed and examined in the clinic, it is envisaged that smaller or fragment-based ADCs will expand oncological applications.
Abstract: Introduction: Antibody drug conjugates now make up a significant fraction of biopharma’s oncology pipeline due to great advances in the understanding of the three key components and how they should be optimised together. With this clinical success comes innovation to produce new enabling technologies that can deliver more effective antibody-drug conjugates (ADCs) with a larger therapeutic index.Areas covered: There are many reviews that discuss the various strategies for ADCs design but the last 5 years or so have witnessed the emergence of a number of different antibody formats compete with the standard whole immunoglobulin. Using published research, patent applications and conference disclosures, the authors review the many antibody and antibody-like formats, discussing innovations in protein engineering and how these new formats impact on the conjugation strategy and ultimately the performance. The alternative chemistries that are now available offer new linkages, stability profiles, drug:antibody rati...
TL;DR: This article focuses on reviewing ensemble docking as an approximate but inexpensive method to incorporate receptor flexibility in molecular docking, and outlines key features and recent advances of this method and points out problem areas that need to be addressed.
Abstract: Introduction: Molecular docking has become a popular method for virtual screening. Docking small molecules to a rigid biological receptor is fast but could produce many false negatives and identify less diverse compounds. Flexible receptor docking has alleviated this problem.Areas covered: This article focuses on reviewing ensemble docking as an approximate but inexpensive method to incorporate receptor flexibility in molecular docking. It outlines key features and recent advances of this method and points out problem areas that need to be addressed to make it even more useful in drug discovery.Expert opinion: Among the different methods introduced for flexible receptor docking, ensemble docking represents one of the most popular approaches, especially for high-throughput virtual screening. One can generate structural ensembles by using experimental structures, by structural modeling and by various types of molecular simulations. In building a structural ensemble, a judicious choice of the structures to b...
TL;DR: While omalizumab is the only mAb available for treating allergic asthma, the authors anticipate that new mAbs will emerge in the future that overcome omalIZumab’s current limitations.
Abstract: Introduction: The evolution in immunological methods used to assess human allergic diseases has led to the identification of immunoglobulin E (IgE) as a diagnostic biomarker and a potential therapeutic target. Innovative technologies in molecular biology and immunogenetics contributed to the development of a selective blocking agent, disclosing new therapeutic perspectives in the treatment of allergic asthma. Omalizumab is the most advanced humanized anti-IgE monoclonal antibody that specifically binds serum-free IgE. Omalizumab also interrupts the allergic cascade by preventing binding of IgE with FcϵRI receptors on mast cells, basophils, antigen-presenting cells and other inflammatory cells.Areas covered: This review discusses the discovery strategy and preclinical development of omalizumab. Furthermore, it also provides a clinical overview of the key trials leading to its launch and a detailed analysis of safety and post-marketing data.Expert opinion: The clinical efficacy of omalizumab in allergic ast...
TL;DR: The authors analyze all of the main steps leading to the global approval of sofosbuvir, a direct-acting antiviral (DAAs) that represents the backbone of several effective regimens, in combination with IFN or with other DAAs (IFN-free therapies).
Abstract: Introduction: Hepatitis C virus (HCV) infection is a worldwide health problem, whose management has been revolutionized after the availability of sofosbuvir, a direct-acting antiviral (DAAs). Sofosbuvir is a HCV NS5B polymerase inhibitor. Antiviral regimens including sofosbuvir are associated with success rates >90%, even in the case of “difficult-to-treat” patients such as subjects with liver cirrhosis as well as prior null response to IFN and ribavirin.Areas covered: This drug discovery case history focuses on the pre-clinical and clinical development of sofosbuvir. The authors analyze all of the main steps leading to the global approval of sofosbuvir. The paper also highlights the encouraging data from the subsequent trials wherein sofosbuvir was tested in combination with other DAAs (IFN- and often ribavirin-free regimens) and from first real life studies.Expert opinion: Sofosbuvir is a very powerful weapon in the new armamentarium against HCV. Thanks to its valuable features including its pangenotypi...
TL;DR: The principle of privileged scaffolds has greatly enhanced and empowered current lead generation technologies and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands is reviewed.
Abstract: Introduction: The term “privileged scaffold” was coined in 1988 and the strategy was to construct high-affinity ligands from core structures that can bind more than one receptor. Since then, the privileged scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms.Areas covered: In this review, the authors discuss the applications of the privileged scaffold concept in current lead generation. Specifically, the authors cover the role that privileged scaffolds have played in the mass production of compounds to feed high-throughput screening (HTS) and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands. It is not the intention of the authors to review all privileged scaffolds known to date. Rather, the aim of this review is to highlight the strategic value of the concept of privileged scaffolds in various contemporary lead generation platforms.Expert opinion: The privileged scaf...
TL;DR: There is an urgent need to invent and employ unconventional strategies for antimicrobial drug development to tackle the rising global threats imposed by the spread of antimicrobial resistance.
Abstract: Introduction: In recent years, infections caused by multidrug-resistant bacterial pathogens have become a huge issue to public healthcare systems. Indeed, the misuse of antibiotics has led to, over the past 30 years, the emergence of a number of resistant bacterial strains including Staphylococcus aureus, Neisseria gonorrhoeae, Escherichia coli and Mycobacterium tuberculosis. Unfortunately, efforts to produce new antibiotics have not been sufficient to cope with the emergence of these new antibiotic-resistant (AR) strains.Areas covered: There is an urgent need to invent and employ unconventional strategies for antimicrobial drug development to tackle the rising global threats imposed by the spread of antimicrobial resistance. Herein, the authors discuss these novel design strategies and provide their expert perspective on the subject.Expert opinion: To deal with the growing threat of AR, it is important to cut down the use of antibiotics to the very minimum to diminish the risk of unknown drug-resistant b...
TL;DR: This review summarizes the recent efforts in the drug development of HDACs and their potential application as therapeutic agents in cancerous, neurological, inflammatory and viral diseases and their use in combination with other epigenetic target modulators for a synergistic effect.
Abstract: Introduction: Histone deacetylases (HDACs) are key players in the mediation of gene expression for both cancerous and noncancerous malignancies. Overexpression of these enzymes has been demonstrated in numerous types of cancer with some enzyme isoforms also involved in neurological, inflammatory and viral pathologies. Hence, the development of HDAC inhibitors (HDACis) represents a promising approach for their treatment. Numerous chemical entities have been studied in the recent years and some of them have reached clinical trials.Areas covered: This review summarizes the recent efforts in the drug development of HDACis and their potential application as therapeutic agents in cancerous, neurological, inflammatory and viral diseases.Expert opinion: The development of novel potent and selective HDACis is ongoing. However, increased scientific effort is needed to aid the fight of specific types of cancerous or noncancerous disease with more selective agents required to avoid side effects during therapy. An int...
TL;DR: This review describes how structural knowledge gained from X-ray crystallography has been used to advance other biophysical methods for structure determination and how a combination of structural and biochemical/biophysical methods may improve the understanding of biological processes and interactions.
Abstract: Introduction: Macromolecular X-ray crystallography has been the primary methodology for determining the three-dimensional structures of proteins, nucleic acids and viruses. Structural information has paved the way for structure-guided drug discovery and laid the foundations for structural bioinformatics. However, X-ray crystallography still has a few fundamental limitations, some of which may be overcome and complemented using emerging methods and technologies in other areas of structural biology.Areas covered: This review describes how structural knowledge gained from X-ray crystallography has been used to advance other biophysical methods for structure determination (and vice versa). This article also covers current practices for integrating data generated by other biochemical and biophysical methods with those obtained from X-ray crystallography. Finally, the authors articulate their vision about how a combination of structural and biochemical/biophysical methods may improve our understanding of biolog...
TL;DR: In this review, the authors present recent advances in visualization of the chemical space in the framework of current general understanding of this topic, with attention given to such methods as van Krevelen diagrams, descriptor plots, principal components analysis (PCA), self-organizing maps (SOM), generative topographic mapping (GTM), graph and network-based approaches.
Abstract: Introduction: The concept of ‘chemical space’ reveals itself in two forms: the discrete set of all possible molecules, and multi-dimensional descriptor space encompassing all the possible molecules. Approaches based on this concept are widely used for the analysis and enumeration of compound databases, library design, and structure–activity relationships (SAR) and landscape studies. Visual representations of chemical space differ in their applicability domains and features and require expert knowledge for choosing the right tool for a particular problem.Areas covered: In this review, the authors present recent advances in visualization of the chemical space in the framework of current general understanding of this topic. Attention is given to such methods as van Krevelen diagrams, descriptor plots, principal components analysis (PCA), self-organizing maps (SOM), generative topographic mapping (GTM), graph and network-based approaches. Notable application examples are provided.Expert opinion: With the grow...
TL;DR: This review covers the basics of FA and complementary methods, such as fluorescence lifetime anisotropy and their roles in the drug discovery process, and highlights the factors affecting FA readouts, fluorophore selection and instrumentation.
Abstract: Introduction: Fluorescence anisotropy (FA) is one of the major established methods accepted by industry and regulatory agencies for understanding the mechanisms of drug action and selecting drug candidates utilizing a high-throughput format.Areas covered: This review covers the basics of FA and complementary methods, such as fluorescence lifetime anisotropy and their roles in the drug discovery process. The authors highlight the factors affecting FA readouts, fluorophore selection and instrumentation. Furthermore, the authors describe the recent development of a successful, commercially valuable FA assay for long QT syndrome drug toxicity to illustrate the role that FA can play in the early stages of drug discovery.Expert opinion: Despite the success in drug discovery, the FA-based technique experiences competitive pressure from other homogeneous assays. That being said, FA is an established yet rapidly developing technique, recognized by academic institutions, the pharmaceutical industry and regulatory a...
TL;DR: The general properties and types of foldamers are covered, including highlighted examples of medicinal chemical applications, including antibacterial and cargo molecules, anti-Alzheimer compounds and protein–protein interaction modifiers.
Abstract: Introduction: Foldamers are artificial self-organizing systems with various critical properties: i) a stable and designable secondary structure; ii) a larger molecular surface as compared with ordinary organic drug molecules; iii) appropriate control of the orientation of the side-chain functional groups; iv) resistance against proteolytic degradation, which leads to potentially increased oral bioavailability and a longer serum half-life relative to ordinary α-peptides; and v) the lower conformational freedom may result in increased receptor binding in comparison with the natural analogs.Areas covered: This article covers the general properties and types of foldamers. This includes highlighted examples of medicinal chemical applications, including antibacterial and cargo molecules, anti-Alzheimer compounds and protein–protein interaction modifiers.Expert opinion: Various new foldamers have been created with a range of structures and biological applications. Membrane-acting antibacterial foldamers have bee...
TL;DR: This work focuses on network-based machine learning models and their use in the prediction of novel compound–target interactions both in target-based and phenotype-based drug discovery applications, and suggests the most potent interactions for further experimental or pre-clinical evaluation.
Abstract: Introduction: System-wide identification of both on- and off-targets of chemical probes provides improved understanding of their therapeutic potential and possible adverse effects, thereby accelerating and de-risking drug discovery process. Given the high costs of experimental profiling of the complete target space of drug-like compounds, computational models offer systematic means for guiding these mapping efforts. These models suggest the most potent interactions for further experimental or pre-clinical evaluation both in cell line models and in patient-derived material.Areas covered: The authors focus here on network-based machine learning models and their use in the prediction of novel compound–target interactions both in target-based and phenotype-based drug discovery applications. While currently being used mainly in complementing the experimentally mapped compound–target networks for drug repurposing applications, such as extending the target space of already approved drugs, these network pharmacol...
TL;DR: The authors believe that the greatest therapeutic benefit might come through leukemic cells that are in direct contact with the inhibitor in the blood stream, and discuss the progress in the development of small-molecule Plk1 inhibitors.
Abstract: The Polo-like kinase 1 (Plk1) plays a key role in regulating a broad spectrum of critical cell cycle events. Plk1 is a marker of cellular proliferation and has prognostic potential in different types of human tumors. In a series of preclinical studies, Plk1 has been validated as a cancer target. This prompted many pharmaceutical companies to develop small-molecule inhibitors targeting the classical ATP-binding site of Plk1 for anticancer drug development. Recently, FDA has granted a Breakthrough Therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. Remarkably, a new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the Polo-box domain, is currently being tested preclinically. Since various ATP-competitive compounds of Plk1 inhibit also the activities of Plk2 and Plk3, which act as tumor suppressors, the roles of closely related Plk-family members in cancer cells need to be considered carefully. In this article, the authors highlight recent insights into the biology of Plks in cancer cells and discuss the progress in the development of small-molecule Plk1 inhibitors. The authors believe that the greatest therapeutic benefit might come through leukemic cells that are in direct contact with the inhibitor in the blood stream. The identification of biomarkers and studies that document Plk activities in treated patients would also be beneficial to better understand the role of Plk inhibition in tumor development and anticancer therapy.
TL;DR: It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripoline stem cells in drug discovery programs.
Abstract: Introduction: Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells.Areas covered: In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field.Expert opinion: The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Huma...
TL;DR: The authors explore the available computational tools in the context of the extant of big data that has borne out via advents of the Omics revolution in order to give drug discovery scientists the best opportunity.
Abstract: Drug discovery is an iterative cycle of identifying promising hits followed by lead optimization via bioisosteric replacements. In the search for compounds affording good bioactivity, equal importance should also be placed on achieving those with favorable pharmacokinetic properties. Thus, the balance and realization of both key properties is an intricate problem that requires great caution. In this editorial, the authors explore the available computational tools in the context of the extant of big data that has borne out via advents of the Omics revolution. As such, the selection of appropriate computational tools for analyzing the vast number of chemical libraries, target proteins and interactomes is the first step toward maximizing the chance for success. However, in order to realize this, it is also necessary to have a solid foundation on the big concepts of drug discovery as well as knowing which tools are available in order to give drug discovery scientists the best opportunity.
TL;DR: Future efforts targeting T3SS to prevent or treat bacterial infections should focus on deciphering the mode of action of inhibitors and on target-based approaches.
Abstract: Introduction: The type III secretion system (T3SS) injectisome is an essential virulence mechanism used by many bacterial pathogens to inject host cells with effector proteins. Bacteria harboring T3SSs can cause significant disease in humans. As bacterial antibiotic resistance is a major concern, alternative prophylaxis and therapeutics are needed and T3SSs are a target for anti-virulence drugs. Areas covered: In this article, the authors review whole-cell-based high-throughput screens (HTSs), which have been the main approach used to identify small molecules inhibiting T3SSs. The authors review this in the context of particular characteristics of T3SSs. Furthermore, they also describe the follow-up approaches used to study the inhibitors found. The authors also highlight target-based approaches to find inhibitors of specific T3SS components. Finally, the authors briefly review strategies used to find inhibitors of effectors or of effector-activated host cell pathways, and approaches based on T3SSs for ac...
TL;DR: Despite its cost and significant side-effect profile, sorafenib should be considered for the treatment of RAI-refractory advanced DTC patients following evaluation of their individual risk–benefit stratification, the authors say.
Abstract: Introduction: Although the prognosis for most differentiated thyroid cancers (DTCs) remains excellent, recurrence and insensitivity to radioactive iodine (RAI) lead to therapeutic challenges and poorer outcomes In defining the pathogenesis of DTC, multiple genetic alterations have been identified in key pathways focused around receptor tyrosine kinases (RTKs) and the MAPK cascade Sorafenib was specifically developed to target rapidly accelerated fibrosarcoma (RAF) kinase in the MAPK pathway It has been shown, however, to have potent inhibition of several key RTKs, RAF kinase and the V600E BRAF mutation, gaining FDA approval in November 2013 for advanced RAI-refractory DTCAreas covered: The authors provide a review of the targeted RAF kinase discovery strategy as well as the preclinical and clinical development of sorafenib, leading to FDA approval of DTC The authors also provide some insight into the clinical use of sorafenib and look at important considerations for treatmentExpert opinion: Sorafeni
TL;DR: The authors discuss current methods for the culturing of cells in 3D as well as approaches for the imaging of whole-animal models and 3D cultures that are amenable to high-throughput settings and could be implemented to support drug discovery campaigns.
Abstract: Introduction: High-resolution microscopy using fluorescent probes is a powerful tool to investigate individual cell structure and function, cell subpopulations and mechanisms underlying cellular responses to drugs. Additionally, responses to drugs more closely resemble those seen in vivo when cells are physically connected in three-dimensional (3D) systems (either 3D cell cultures or whole organisms), as opposed to traditional monolayer cultures. Combined, the use of imaging-based 3D models in the early stages of drug development has the potential to generate biologically relevant data that will increase the likelihood of success for drug candidates in human studies.Areas covered: The authors discuss current methods for the culturing of cells in 3D as well as approaches for the imaging of whole-animal models and 3D cultures that are amenable to high-throughput settings and could be implemented to support drug discovery campaigns. Furthermore, they provide critical considerations when discussing imaging th...
TL;DR: The most advanced CA IX inhibitors candidates, which demonstrate antimetastatic activity in breast cancer, are the sulfonamides, with one compound (SLC-0111) currently in Phase I clinical development, and the fact that this first inhibitor has progressed could increase interest in the development of conceptually novel antitumor/antimetastic drugs belonging to the CA inhibitors class.
Abstract: Introduction: Carbonic anhydrase (CA) IX is one of the proteins that are involved in cancerogenesis in hypoxic breast tumors. Indeed, it is present in high amounts in hypoxic tumor cells, where it plays a crucial role in metabolic reprogramming due to the scarcity of oxygen, triggered by the hypoxia inducible factor 1 transcription factor. In such tumors, CA IX is involved, along with other proteins, in tumor pH regulation and its survival in a harsh environment (including hypoxia and acidity). CA IX is also validated as an imaging and treatment target for hypoxic tumors and metastasis.Areas covered: In this review, the authors highlight the wealth of CA IX inhibitors currently in the literature. This includes the two most investigated classes of compounds being the sulfonamides and the coumarins, including their isosteres.Expert opinion: The most advanced CA IX inhibitors candidates, which demonstrate antimetastatic activity in breast cancer, are the sulfonamides, with one compound (SLC-0111) currently i...