Expert Opinion on Drug Discovery最新文献

Introduction: Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.

Areas covered: The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens. All these models have individual advantages, disadvantages and limitations that need to be considered depending on the desired application.

Expert opinion: In addition to potential cost limitations, availability of BTC cell types, time required for model establishment and growth success rate, the individual models differently reflect relevant characteristics such as tumor heterogeneity, spatial tumor-stroma microenvironment interactions, metabolic and nutritional gradients and immunological interactions. Therefore, a consequent combination of different models may be required to improve clinical study outcomes by strengthening the preclinical data basis.

Introduction: Macromolecular X-ray crystallography (XRC), nuclear magnetic resonance (NMR), and cryo-electron microscopy (cryoEM) are the primary techniques for determining atomic-level, three-dimensional structures of macromolecules essential for drug discovery. With advancements in artificial intelligence (AI) and cryoEM, the Protein Data Bank (PDB) is solidifying its role as a key resource for 3D macromolecular structures. These developments underscore the growing need for enhanced quality metrics and robust validation standards for experimental structures.

Areas covered: This review examines recent advancements in cryoEM for drug discovery, analyzing structure quality metrics, resolution improvements, metal-ligand and water molecule identification, and refinement software. It compares cryoEM with other techniques like XRC and NMR, emphasizing the global expansion of cryoEM facilities and its increasing significance in drug discovery.

Expert opinion: CryoEM is revolutionizing structural biology and drug discovery, particularly for large, complex structures in induced proximity and antibody-antigen interactions. It supports vaccine design, CAR T-cell optimization, gene editing, and gene therapy. Combined with AI, cryoEM enhances particle identification and 3D structure determination. With recent breakthroughs, cryoEM is emerging as a crucial tool in drug discovery, driving the development of new, effective therapies.

Introduction: Leishmaniasis is a significant neglected tropical disease with limited treatment options that urgently requires ongoing efforts in drug discovery. Recent advances have focused on the development of new assays and methods to identify effective therapeutic candidates.

Areas covered: This review explores recent trends and methodologies in leishmaniasis drug discovery, with a particular focus on in silico and in vitro studies, as well as in vivo validation, using animal models. A detailed analysis of recent studies was provided, discussing the methodologies employed, such as manual and automated parasite quantification, and the use of fluorescence and luminescence-based techniques. Additionally, global research trends were analyzed, highlighting the leading countries in scientific output and the collaborative efforts driving advancements in this field.

Expert opinion: The field of leishmaniasis drug discovery has rapidly progressed in the last years, but the lack of standardized methodologies and limited in vivo validation remain significant hurdles. To advance promising treatments to clinical trials, cross-validation of preclinical findings and interdisciplinary collaboration are essential. Increased funding and global partnerships are also crucial to accelerate the discovery and development of alternative and effective therapies.

Introduction: Glycosylation is an essential enzymatic process of building glycan structures that occur mainly within the cell and gives rise to a diversity of cell surface and secreted glycoconjugates. These glycoconjugates play vital roles, for instance in cellcell adhesion, interaction and communication, activation of cell surface receptors, inflammatory response and immune recognition. This controlled and wellcoordinated enzymatic process is altered in cancer, leading to the biosynthesis of cancerassociated glycans, which impact glycandependent biological roles.

Areas covered: In this review, the authors discuss the importance of targeting cancerassociated glycans through potent glycan biosynthesis inhibitors. It focuses on the use of analogs, providing an overview of findings involving these in cancer. The highly explored fluorinated monosaccharide analogs targeting aberrant glycosylation are described, aiming to inspire advances in the field.

Expert opinion: Altered glycosylation, such as increased sialylation and fucosylation, is a feature in cancer and has been shown to play key roles in several malignant properties of cancer cells. Strategies aiming at remodeling cancer cells´ glycome are emerging and present a huge potential for cancer therapy. Fluorinated monosaccharides have been gathering promising preclinical results as novel cancer drugs. Nevertheless, cancer specific targeting strategies must be considered to avoid significant sideeffects.

Introduction: The emergence of antibiotic resistance among the clinically important bacterial pathogens has increased healthcare costs and reduced patient safety and quality of life. Lantibiotics is a large class of ribosomally synthesized, and posttranslationally modified peptides have been the primary focus of numerous research aimed at discovering compounds for treating bacterial infections.

Areas covered: The article explains the most up to date hierarchy of methods followed in the field for high throughput screening of lantibiotics/analogs with improved therapeutic properties. Herein, we explain how the structure and the biosynthesis of lantibiotics can be manipulated for the expansion of the horizon of lantibiotic potency. Furthermore, we discuss the lantibiotic analogs that have demonstrated the efficacy against bacterial pathogens of interest in animal models.

Expert opinion: In this current age of rapidly advancing antimicrobial resistance, there is a dire need for the development of therapeutic agents that possess distinct mechanisms of action to existing modes of treatment. Recent advances in the understanding of many of the lantibiotic biosynthesis systems and the discovery of new analogs with superior properties to the native compound may have paved the way for the development of a much-needed novel potent class of antibiotic.

Introduction: Hypertension remains a major public health concern, with significant morbidity and mortality worldwide. Despite the availability of various antihypertensive medications, blood pressure control remains suboptimal in many individuals. During the last decades, K_V7.4 and K_V7.5, which were already known from the view of neuronal regulation, emerged as possible important players in the regulation of vascular tone and blood pressure.

Areas covered: This review covers physiological functions and current advancements in the development of K_V7.4 and K_V7.5 channel modulators. The authors highlight the structural elements likely to be important for the future design of K_V7 subtype-selective modulators, underscoring their potential as an innovative hypertension treatment.

Expert opinion: Extensive research has been focused on targeting neuronal K_V7.2 and K_V7.3 channels, while K_V7.4 and K_V7.5 attracted less attention. Many of the developed compounds represent derivatives of flupirtine or retigabine, whereby subtype channel selectivity has only been demonstrated for a handful of individual compounds. Novel substances address additional sites within the binding pocket by incorporating new functional groups. A comprehensive and systematic evaluation of a compound set with significant subtype selectivity should be performed. The discovery of new highly active, less toxic, and selective compounds, therefore, remains the goal of further research in the coming years.

Introduction: Antisense oligonucleotide (ASO) was established as a viable therapeutic option for genetic disorders. ASOs can target RNAs implicated in various diseases, including upregulated mRNA and pre-mRNA undergoing abnormal alternative splicing events. Therapeutic applications of ASOs have been proven with the Food and Drug Administration approval of several drugs in recent years. Earlier enzymatic stability and delivery remains a big challenge for ASOs. Introducing new chemical modifications and new formulations resolving the issues related to the nuclease stability and delivery of the ASOs. Excitingly, ASOs-based bioconjugates that target the hepatocyte have gained much attraction. Efforts are ongoing to increase the therapeutic application of the ASOs to the extrahepatic tissue as well.

Area covered: We have briefly discussed the mechanism of ASOs, the development of new chemistries, and delivery strategies for ASO-based drug discovery and development. The discussion focuses more on the already approved ASOs and those in the clinical development stage.

Expert opinion: To expand the clinical application of ASOs, continuous effort is required to develop precise delivery strategies for targeting extrahepatic tissue to minimize the off-target effects.

Introduction: Decades of research on cannabidiol (CBD) have identified thousands of purported cellular effects, and many of these have been proposed to correlate with a vast therapeutic potential. Yet despite the large volume of findings fueling broad optimism in this regard, few have translated into any demonstrable clinical benefit or even notable side effects. Therein resides the great paradox of CBD: a drug that appears to affect almost everything in vitro does not clearly do much of anything in a clinical setting.

Areas covered: Comparative critical evaluation of literature searched in PubMed and Google Scholar discovers multiple instances of inconsistent and contradictory findings regarding the pharmacology and clinical effects of CBD, as well as several uncelebrated reports that suggest potential explanations for these observations. Many of those effects attributed to the ostensible pharmacologic activity of cannabidiol are almost certainly the product of false-positive experimental results and artifactual findings that are unlikely to be realized under physiologic conditions.

Expert opinion: Concerns regarding the physiological relevance and translational potential of in vitro findings across the field of cannabinoid research are both far-reaching and demanding of attention in the form of appropriate experimental controls that remain almost universally absent.

Introduction: Mapping the interactions between pharmaceutical compounds and their molecular targets is a fundamental aspect of drug discovery and repurposing. Drug-target interactions are important for elucidating mechanisms of action and optimizing drug efficacy and safety profiles. Several computational methods have been developed to systematically predict drug-target interactions. However, computational and experimental validation of the drug-target predictions greatly vary across the studies.

Areas covered: Through a PubMed query, a corpus comprising 3,286 articles on drug-target interaction prediction published within the past decade was covered. Natural language processing was used for automated abstract classification to study the evolution of computational methods, validation strategies and performance assessment metrics in the 3,286 articles. Additionally, a manual analysis of 259 studies that performed experimental validation of computational predictions revealed prevalent experimental protocols.

Expert opinion: Starting from 2014, there has been a noticeable increase in articles focusing on drug-target interaction prediction. Docking and regression stands out as the most commonly used techniques among computational methods, and cross-validation is frequently employed as the computational validation strategy. Testing the predictions using multiple, orthogonal validation strategies is recommended and should be reported for the specific target prediction applications. Experimental validation remains relatively rare and should be performed more routinely to evaluate biological relevance of predictions.