Drug Discovery Today最新文献

Metalloenzymes are important therapeutic targets for a variety of human diseases. Computational approaches have recently emerged as effective tools to understand metal-ligand interactions and expand the structural diversity of both metalloenzyme inhibitors (MIs) and metal-binding pharmacophores (MBPs). In this review, we highlight key advances in currently available fine-tuning modeling methods and data-driven cheminformatic approaches. We also discuss major challenges to the recognition of novel MBPs and MIs. The evidence provided herein could expedite future computational efforts to guide metalloenzyme-based drug discovery.

Previous analyses provide an industry benchmark of ∼10% for the success rate in clinical development. However, prior analyses were limited by a narrow timeframe, a diverse research focus, biases in phase-to-phase transition methodology or a focus on specific use cases. We calculated unbiased input:output ratios (Phase I to FDA new drug approval) to analyze the likelihood of first approval using data from clinicaltrials.gov, encompassing a total of 2092 active ingredients, 19 927 clinical trials conducted by 18 leading pharmaceutical companies (2006-2022) and 274 new drug approvals. Our study reveals an average likelihood of first approval rate of 14.3% across leading research-based pharmaceutical companies, broadly ranging from 8% to 23%.

Cancer remains a global health threat, with traditional treatments limited by adverse effects and drug resistance. Nanozyme-based catalytic therapy with high stability and controllable activity provides targeted and specific in situ tumor treatment to address these challenges. More intriguingly, the tremendous advances in nanotechnology have enabled nanozymes to rival the catalytic activity of natural enzymes, presenting an exciting opportunity for innovating antitumor nanodrugs. This review systematically summarizes the latest progresses in nanozyme-based anticancer catalytic therapy, with a particular focus on various synergistic antitumor strategies, including other functional enzymes, drugs, exogenous stimuli and radiotherapy. These combinations not only enhance the efficacy of cancer treatment and reduce systemic toxicity but also offer insights into the development of potent antitumor nanodrugs.

Increasing evidence from fluid biopsies suggests activation and injury of glial cells in epilepsy. The prevalence of clinical and subclinical seizures in neurodegenerative conditions such as Alzheimer's disease, frontotemporal dementia, and others merits review and comparison of the effects of seizures on glial markers in epilepsy and neurodegenerative diseases with concomitant seizures. Herein, we revisit preclinical and clinical reports of alterations in glial proteins in cerebrospinal fluid and blood associated with various types of epilepsy. We consider shared and distinct characteristics of changes in different age groups and sexes, in humans and animal models of epilepsy, and compare them with those reported in biofluids in neurodegenerative diseases. Our analysis indicates a significant overlap of glial response in these prevalent neurological conditions.

As technology evolves and medical needs diversify, the pharmaceutical industry must accelerate its openness. This study analysed interorganizational alliances in R&D for the new modality of oligonucleotide therapeutics in order to explore the requirements for establishing new markets. The results confirmed that the market has developed in stages, employing open innovation for different purposes according to technological progress. At each stage, it was crucial to form platforms among biotech companies on the drug discovery side, among pharmaceutical companies on the regulatory side and among contract development manufacturing organizations (CDMOs) on the manufacturing side. These findings clarify the dynamics of open innovation in the biopharmaceutical industry and provide strategic implications for sustainable value creation in drug R&D.

Cardiorenal syndrome (CRS) is an interdependent dysfunction of the heart and kidneys, where failure in one organ precipitates failure in the other. The pathophysiology involves sustained renin-angiotensin-aldosterone-system (RAAS) activation, mitochondrial dysfunction, inflammation, fibrosis, oxidative stress and tissue remodeling, culminating in organ dysfunction. Existing therapies targeting the RAAS, diuretics and other agents have limitations, including diuretic resistance and compensatory sodium reabsorption. Therefore, there is a pressing need for novel druggable targets involved in CRS pathogenesis. This review addresses the challenges of existing treatments and emphasizes the importance of discovering new therapeutic targets. It highlights emerging targets such as Klotho, sex-determining region Y box 9 (SOX9), receptor-interacting protein kinase 3 (RIPK3), β-amino-isobutyric acid (BAIBA), thrombospondin-1 (TSP-1), among others, with their potential roles in CRS.

Repurposing off-patent drugs can be a potential source of low-cost treatments for patients with unmet medical needs. Here, we review the proposed new European Union (EU) pharmaceutical legislation in which two articles address drug repurposing. We find certain barriers hindering the adoption of these new incentives by academic and not-for-profit stakeholders, including lack of knowledge on regulatory aspects, pharmacovigilance, and restrictions in data protection. To further empower the intended stakeholders of the legislation, these initiatives can be strengthened by creating additional scientific, regulatory, and health technology assessment (HTA) support for not-for-profit repurposers, and by determining fair data protection periods and pricing policies. To support drug repurposing, Europe should work toward a comprehensive drug-repurposing strategy that fosters the repurposing of generic, shelved, and protected drugs.

The heat shock protein (HSP) 110 family has a key role as a unique class of molecular chaperones maintaining cellular proteostasis in eukaryotes. Abnormal activation of Hsp110 has been implicated in several diseases. Given its important role in pathogenesis, Hsp110 has become a novel drug target for disease diagnosis and targeted therapy. Thus, targeting Hsp110 or its interactions with client proteins offers new therapeutic approaches. Recent studies of small-molecule inhibitors that target Hsp110 in vitro and in vivo have yielded encouraging results. In this review, we provide an overview of novel therapeutics targeting Hsp110, mainly inhibitors of protein-protein interactions (PPIs), together with a brief discussion of the relevant challenges, opportunities, and future directions.

The contributions of academic drug discovery are well characterised in the US context but less well understood elsewhere. This paper provides a UK perspective, focusing on the activities of Drug Discovery Units (DDUs). These units have established themselves as coordinators of translational research, working at the early stages of the drug pipeline to link up the academic and industry capabilities needed to take drug candidates towards the market. Drawing on publicly available sources and interviews with staff from a range of DDUs, the paper reveals DDUs' progress and challenges. While most DDUs have established collaborations with industry, the goal of taking drugs to market remains some way ahead for the vast majority, while sustainable funding is increasingly a concern.

Magnetic polymeric nanocomposites are a modern class of materials in which magnetic nanoparticles are embedded in a polymeric matrix. This combination of magnetic responsiveness and tuneable properties bestows versatility on this class of polymer nanocomposite material, which has potentially broad applications in drug delivery, imaging, environmental remediation and beyond. This review covers the uses of magnetic polymeric nanocomposites in drug delivery, discussing magnetic micelles, magnetic liposomes, magnetic hydrogels, magnetic sponges, magnetic mesoporous silica nanoparticles, magnetic microrobots, magnetic elastomers and magnetic scaffolds. The focus is on the role that might be played by magnetic nanocomposites as an interface between the magnetic and polymeric domains in the establishment of a new generation of advanced materials.