Current topics in medicinal chemistry最新文献

Background: Strokes represent a significant global health concern, with ischemic stroke being the most prevalent and deadly form. The pathogenesis of ischemic stroke involves complex mechanisms, including excitotoxicity, oxidative stress, and cell death. This study presents a computational design of novel GluN2B-selective N-Methyl-D-Aspartate receptor antagonists with potential therapeutic applications in neurodegenerative disorders.

Methods: 3D-Quantitative Structure-Activity Relationship (QSAR) model and molecular dynamics simulations were employed to design novel NMDA receptor antagonists. A dataset of 53 derivatives was analyzed using structure-based virtual screening, molecular docking, and pharmacophore modeling.

Results: Molecular docking and dynamics simulations confirmed the binding affinity and dynamic behavior of the designed compounds, providing insights into their potential as therapeutic agents. We identified lead compound 75 with high predicted affinity and selectivity for GluN2Bcontaining receptors. Drug-likeness assessment, synthetic accessibility evaluation, and molecular dynamics simulations confirmed favorable pharmacokinetic properties and target engagement stability.

Conclusion: These findings provide a rational framework for the development of selective NMDA receptor antagonists with improved safety and efficacy profiles.

Liver cancer is a highly aggressive malignancy, and bone metastasis is a severe complication that negatively affects prognosis and quality of life. However, the molecular mechanisms underlying liver cancer bone metastasis remain poorly understood. This review examined recent advances related to epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs), and liver cancer stem cells (LCSCs), with a focus on surface markers, interactions within bone marrow (BM) niche, and relevant signaling pathways. Liver cancer bone metastasis is driven by EMT activation, CTC dissemination, and LCSC colonization in BM niches. Surface markers such as CD133, CD44, CD90, CD13, EpCAM, and OV6 contribute to tumor heterogeneity, dormancy, and therapy resistance. Key processes such as BM homing, osteolysis, and immune suppression are regulated through the osteoblast-osteoclast-cancer stem cell (OB-OC-CSC) axis and CXCL12-CXCR4 signaling. Dormancy-regulating molecules, including Annexin II, GAS6, osteopontin, TSP-1, tenascin C, and fibronectin, further determine CSCs' quiescence or reactivation. These insights highlighted the complexity of liver cancer bone metastasis, and suggested potential therapeutic strategies targeting EMT, LCSCs, and OB-OC-CSC crosstalk. Future studies are encouraged to validate marker functions in clinical cohorts, elucidate dormancy-exit mechanisms, and explore immunomodulatory interventions to overcome microenvironment-mediated resistance.

Cancer is a widespread disease that often causes severe pain, significantly reducing patients’ quality of life and increasing the overall burden of the illness. Managing cancer pain effectively remains a major clinical challenge. Metabolism is a fundamental biological process that involves both the breaking down of substances to produce energy (catabolism) and the building of complex molecules (anabolism). Cancer cells exhibit altered energy metabolism, including glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism. Emerging research suggests that these metabolic changes can amplify cancer pain through specific signalling pathways, such as AMPK and PI3K/AKT. Targeting these metabolic pathways offers a promising approach for pain relief. This review explores the link between cancer pain and energy metabolism, highlighting potential new therapeutic strategies aimed at metabolic targets.

Treatment of neurodegenerative diseases aims to slow disease progression, alleviate symptoms, and improve life quality. Adipose-Derived Stem Cells (ADSCs) have emerged as a promising treatment for neurodegenerative diseases that can be easily obtained from adipose tissues. Their abundance, accessibility, and potential for multilinear differentiation make them an attractive candidate for regenerative medicine. ADSCs can release neurotrophic factors, modulate neuroinflammation, and potentially differentiate into neurons, giving hope for neuronal repair and replacement. Preclinical studies have shown the efficacy of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and spinal cord injuries. ADSC has demonstrated the potential to improve functional results, promote neurogenesis, induce tissue integrity, and reduce neuron loss. Clinical trials are still underway, but evidence of the effectiveness of ADSC in neurodegeneration is still being developed. The first clinical studies focused on safety and feasibility and achieved promising results. Optimizing cell transmission, controlling tumor growth, standardizing treatment protocols and such challenges remain. Current research is aimed at addressing these obstacles and transforming ADSC therapy into a widespread clinical practice. This review focuses on the characteristics, problems, and future approaches of ADSC in the context of neurodegenerative diseases and therapeutic processes.

1,3,4-Thiadiazole is a multiform heterocyclic compound whose expansion in the field of medicinal chemistry is due to its unique structure and a variety of biological activities. The fivemembered ring system which contains sulfur and nitrogen atoms and is a hallmark scaffold for the manufacture of pioneering therapeutic agents, is the basic element of this compound. The 1,3,4- thiadiazole group exhibits a wide range of pharmacological activities, including antimicrobials, anti-inflammatories, anticonvulsants, antivirals, and antioxidants. This compound is a great candidate for drug discovery as it is a simple molecule subject to synthesis and interact with many different targets found in organisms. This paper aims to review recent research findings on this nucleus, highlighting the structural modifications of various thiadiazole derivatives for diverse pharmacological activities. Furthermore, this review also examines patents from 2019 to 2024 on thiadiazole derivatives for their applications in various diseases. Through the explication of the latest advancements and the comment on new trends, this study spotlights the capability of 1,3,4- thiadiazole as a core ring for the advancement of next-generation drugs.

Oxidative stress plays a critical role in many diseases, making it essential to study its impact on disease progression. However, clinical trials have many limitations and, in some cases, may not be possible at all. In this case, the development of in vivo models is highly anticipated. This is especially relevant for neurodegenerative diseases. Drosophila melanogaster models have a number of advantages over many other animal models, including the availability and costeffectiveness of breeding, the accumulated knowledge of the Drosophila genome, and the ability to manipulate a large number of individuals. The latter allows for rapid screening and in-depth studies of potential therapeutic agents, including natural compounds with antioxidant activity. This review describes genetic models of such pathologies as Parkinson's disease, Huntington's disease, Alzheimer's disease and hereditary spastic paraplegia created on Drosophila melanogaster. Studies conducted on such models are presented with an emphasis on the role of oxidative stress analysis. Oxidative stress is proven to be a link between neurodegenerative and metabolic diseases. In addition, studies on Drosophila melanogaster have been analyzed, in which the prospects of natural compounds as therapeutic agents for neurodegenerative and metabolic diseases have been demonstrated.

Introduction: Schizophrenia is a heterogeneous chronic brain disorder driven by multiple pathophysiological processes. While dopaminergic theories dominate current therapies, emerging evidence highlights glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDAR) hypofunction, as a key mechanism alongside dopaminergic, serotonergic, and neurodevelopmental pathways. This article synthesizes mechanistic insights, focusing on neurotransmitter disruptions, oxidative stress, neuroinflammation, and Wnt signaling, to elucidate the clinical diversity of schizophrenia and identify biomarkers for precise diagnostics and therapeutics.

Methods: A comprehensive literature search was conducted using Web of Science, Scopus, Google Scholar, and PubMed, with keywords including "schizophrenia," "psychosis," "pathophysiology," "mechanism," and "biomarker." Studies were selected to explore NMDAR hypofunction, glutamatergic dysregulation, and associated signaling pathways, integrating preclinical and human data to map circuit-based interactions and biomarker profiles.

Results: We present a novel circuit-based model of schizophrenia pathophysiology, centered on NMDAR hypofunction and glutamatergic dysregulation, integrating dopaminergic, GABAergic, and inflammatory pathways. Key biomarkers, including inflammatory (e.g., high-sensitivity Creactive protein [hs-CRP], interleukin-6 [IL-6]), neurochemical (e.g., brain-derived neurotrophic factor [BDNF]), and functional (e.g., mismatch negativity [MMN]), are categorized by symptomatic domains and clinical stages, providing diagnostic and prognostic insights.

Discussions: The findings underscore NMDAR hypofunction's role in driving schizophrenia's symptomatic spectrum, though its interplay with other pathways highlights the disorder's complexity. Neuronal loss, although not universal, is context-specific (e.g., hippocampal interneurons), complementing functional biomarkers such as MMN. Limitations include the need for robust human validation of biomarkers and broader exploration of non-glutamatergic mechanisms.

Conclusion: Considering the multifaceted nature of the disorder, our emphasis on the NMDAR hypofunction model can help explain many of the synergies involved among the seemingly independent dysregulated events.

Introduction/objective: African swine fever virus poses a persistent threat to the global pork industry owing to its severe impact on animal welfare, the economy, and food security. Currently, no antiviral medicines are available, and biosecurity measures, such as quarantine and culling, have proven insufficient, often resulting in further economic losses. Given the widespread impact of ASFV, there is an urgent need to explore and develop new treatment strategies to mitigate its spread.

Methods: 1,212 secondary metabolites from brown algae were screened using ADMET profiling. Compounds with favorable properties were selected for molecular docking against A179L, an antiapoptotic protein of ASFV. The top-scoring metabolites were further analyzed through molecular dynamics simulations, principal component analysis (PCA), and binding energy calculations.

Results: ADMET profiling identified compounds with drug-like pharmacokinetic properties. Consensus molecular docking using two docking programs predicted the binding poses of the metabolites, and the top ten candidate ligands with the strongest docking scores were selected. We then performed 300 ns molecular dynamics simulations to assess the stability of the protein-ligand complexes, which were further validated through Principal Component Analysis (PCA). Finally, binding energies were estimated using both MMPBSA and MMGBSA approaches, and the key residues involved during binding were identified. All ten final candidate ligands demonstrated stability and favorable binding affinity (-27.78 kcal/mol to -38.58 kcal/mol).

Conclusion: Five compounds (CID: 24796376, sargachromanol G, strictaepoxide, CID: 163107957, and saringosterone) with the strongest binding energies are recommended for in vitro and in vivo testing to validate their potential as therapeutic agents against ASFV.