Chemical Biology & Drug Design最新文献

Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.

This study identifies RGS7 as a pivotal therapeutic target for dexmedetomidine (DEX) in Alzheimer's disease (AD). Bioinformatics revealed RGS7 is downregulated in AD, and in vivo, DEX administration in APP/PS1 mice restored its hippocampal expression and reduced Aβ plaque burden. Molecular docking supports a direct DEX-RGS7 interaction. The study links RGS7 to neuroinflammation, showing AD patients have elevated pro-inflammatory M1 macrophages and reduced follicular helper T cells. RGS7 expression negatively correlates with M1 macrophages and positively with follicular helper T cells. Crucially, RGS7 was found in microglia, suggesting DEX acts via RGS7 within these cells to exert its anti-inflammatory effects. With diagnostic potential (AUC = 0.79), the DEX-RGS7 axis is a promising therapeutic pathway for AD.

Cancer is one of the most complex diseases. Its multidrug resistance and poor prognosis make the development of antitumor drugs still a difficult task. 18β-glycyrrhetinic acid (18β-GA) has shown great potential for tumor prevention and treatment. However, inherent defects, such as low bioavailability, limit its use. Herein, based on a molecular hybridization strategy, two series of α, β-unsaturated carbonyl modified 18β-GA derivatives were synthesized using 18β-GA as the parent nucleus. Among them, compounds 9a, 9g and 9i exhibited the strongest antiproliferative activity, with IC₅₀ values ranging from 1.52 to 3.46 μM against HCT-116, SH-SY5Y and HepG2 cells. The key target of the three active derivatives was predicted to be human STAT3 through reverse target finding. Docking analysis proved that all three derivatives showed strong binding affinity to STAT3 in silico, suggesting potential as STAT3 inhibitors.

Eight thiadiazole-thiophene hybrids 4, 5, 6, and 7 were prepared by incorporating a thiophene ring system into the precursor 2-(cyanomethyl)-1,3,4-thiadiazole compounds 3a and 3b, through different strategic methods. The structures of these hybrids were elucidated using spectral techniques (IR, NMR, and Mass spectrometry). The DFT (B3LYP) modeling of the built hybrids revealed comparable non-planar configurations and HOMO-LUMO composition, covering the full skeleton (π- and π*-orbitals, respectively). The antimicrobial efficacies of the produced analogues were appraised against both Gram (+ve) and (−ve) bacterial pathogens. Analogues 5a, 5b, 6a, and 7b revealed potent activity (MIC 3.125–6.25 μg/mL). Meanwhile, these analogues established moderate to good inhibitory efficiency of DNA gyrase (IC₅₀ = 4.46 ± 0.09–8.38 ± 0.33 μM), where the analogue 5a exhibited the highest activity, very close to the novobiocin (reference drug; IC₅₀ = 4.01 ± 0.03 μM). Moreover, the molecular docking with a target protein PDB: 6FQM has been performed to discover the interaction patterns of synthesized hybrids. Hybrids 5a, 5b, and 4b showed significant binding energies and stable interaction profiles. Furthermore, the investigated hybrids were evaluated for their pharmacokinetic and drug-likeness properties using SwissADME predictions, where compounds 3a and 3b are the most promising drug-like leads among the thiadiazole hybrids.

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. The clinical therapeutic benefits of the second-generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RET^G810R/S/C). Herein, a class of 2-aminopyrazolpyrimidopyridone derivatives as RET^V804M and RET^G810C solvent-front mutant inhibitors were designed and synthesized for overcoming pralsetinib resistance. One of the optimal compounds, 7la, exhibited inhibitory potency against the proliferation of BaF3 cells harboring CCDC6-RET^V804M mutation with IC50 values of 0.271 μM. Interestingly, another one of these series compounds, 7qe, suppressed BaF3 cells harboring CCDC6-RET^V804M and CCDC6-RET^G810C mutations with IC₅₀ values of 0.841 and 0.272 μM, respectively. The compound also dose-dependently suppressed the activation of RET and downstream signals. However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound 7qe might be a promising lead compound for the development of novel RET^V804M and RET^G810C inhibitors overcoming the clinical acquired resistance.

Diabetic nephropathy (DN) is the main reason for the emergence of end-stage renal disease. Both ginkgolide B (GB) and umbilical cord mesenchymal stem cell-derived exosomes can improve DN, but their combination efficacy is unknown. High glucose (HG)-induced SV40-MES13 cells and streptozotocin-injected high-fat diet mice were treated with MSC-Exos alone or in combination with GB. The activities of reactive oxygen species, malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were analyzed by commercial kits. Pro-inflammatory factors tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 were detected by ELISA. Protein levels of collagen I, fibronectin, alpha smooth muscle actin, nuclear factor erythroid-2-related factor 2 (NRF2), heme oxygenase 1 (HO1), and NAD(P)H:quinine oxidoreductase (NQO1) were assessed by western blot. Pathological changes in mouse kidneys were determined by HE, Masson's, and PAS staining. Both MSC-Exos alone and in combination with GB alleviated HG-induced SV40-MES13 cell OxS, inflammation, and fibrosis. Moreover, MSC-Exos alone and in combination with GB attenuated pathological changes and repressed inflammation and fibrosis in DN mice. Importantly, MSC-Exos was less effective than MSC-Exos in combination with GB. Furthermore, GB plus MSC-Exos activated the NRF2/HO1/NQO1 pathway in HG-induced SV40-MES13 cells and DN mouse models. GB plus umbilical cord MSC-Exos attenuates pathological changes in DN via repressing inflammation, oxidative stress, and fibrosis by activating the NRF2/HO1/NQO1 pathway.

The vital process of CO₂ hydration in all living things is catalyzed by carbonic anhydrases (CAs, EC 4.2.1.1), which are actively involved in the control of numerous pathological and physiological situations. A number of coumarin-based sulfonamides (18) were examined as potential CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II, and the transmembrane hCA IX as well as against three fungal CAs: Malassezia globosa (MgCA), Malassezia pachydermatis (MpaCA), and Malassezia restricta (MreCA). Additionally, the binding mechanism of this family of chemicals within the active site of hCA IX was investigated using computational approaches. Compounds showed interesting inhibitory activity mainly against two fungal strains, Malassezia globosa (MgCA) and Malassezia pachydermatis (MpaCA), exceeding in the first case the activity of the reference drug, and in the second, 16 out of 18 showed Ki values lower than acetozolamide. Furthermore, four compounds were more potent against hCA I than AAZ and two against hCA II. Docking studies were used to investigate the binding mode of the most active compounds against human CA isoforms.

Acute respiratory distress syndrome (ARDS) is a severe and critical clinical pulmonary disease. Resveratrol (RES), a non-flavonoid polyphenolic compound, has shown potential therapeutic effects. However, the underlying mechanism of RES treatment for ARDS remains unclear. This study employed network pharmacology to predict potential targets and metabolic pathways involved in RES treatment for ARDS. Molecular docking and experimental validation were performed to confirm key targets and metabolic pathways. A comprehensive database search identified 115 RES-ARDS-related targets. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighted the JAK/STAT pathway, which was further investigated with RES in the treatment of ARDS. Hematoxylin–eosin (HE) staining visualized lung damage. Western blot analysis showed that RES significantly downregulated p-JAK2, NLRP3, IL-18, and p-STAT3 expression (p < 0.05). A variety of animal experiments have substantiated that RES can effectively inhibit inflammation and oxidative stress, and promote blood barrier repair. In conclusion, this study provides new insights into the protective mechanism of RES against ARDS, highlighting its potential as a therapeutic agent.

Drug-target interaction (DTI) prediction plays a vital role in drug discovery. However, traditional experimental methods are often time-consuming and resource-intensive. Recently, deep learning (DL) approaches have emerged as powerful and efficient tools for predicting DTIs. This paper provides a structured overview of these DL-based methods, beginning with a review of feature representation strategies for drugs and proteins, followed by a summary of commonly used datasets and evaluation metrics. The review critically examines various DL architectures, including deep neural networks (DNNs), recurrent neural networks (RNNs), convolutional neural networks (CNNs), graph neural networks (GNNs), and Transformer-based models. Furthermore, we discuss their applications in drug repositioning, drug design, and precision medicine. Finally, we address key challenges such as data scarcity and model interpretability, and highlight future research directions including self-supervised learning and explainable artificial intelligence. This review aims to provide a rigorous synthesis of current advances to inform future developments in DL-based DTI prediction.

Primary Sjogren's syndrome (pSS) presents as a persistent inflammatory condition marked by a spectrum of symptoms and a limited array of conventional therapeutic interventions. Within Traditional Chinese Medicine (TCM), the Qiju Dihuang Pill (QJDHW) stands as a frequently employed prescription for addressing this syndrome, yet the underlying therapeutic mechanisms remain elusive. Traditional Chinese Medicine Systems Pharmacology (TCMSP) and three disease gene databases, DisGnet, GeneCards, and OMIM, were utilized to establish QJDHW targets and pSS-related gene sets. Cytoscape was used to construct Protein–protein interaction (PPI) and active compound-target networks, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment via the DAVID database. Molecular docking was conducted with AutoDock Vina, and in vitro experiments verified the key findings. A total of 62 overlapping targets were identified. Network analysis revealed quercetin and kaempferol as major active compounds. KEGG enrichment indicated that QJDHW may exert its therapeutic effects by modulating the immune-inflammatory response. Four key targets, namely NFKBIA, IL-6, JUN, and IL-1B, were identified as the central mediators. Molecular docking analysis confirmed their binding affinity with the major active compounds. In vitro assays further confirmed that quercetin and kaempferol suppressed the mRNA expression of key inflammation-related factors, including IL-6, IL-1B, JUN, and NFKB, while reducing IL-6 and IL-1B protein levels and significantly inhibiting the phosphorylation of JUN and NFKB. Collectively, the integration of network pharmacology and experimental validation demonstrated that QJDHW exerts anti-inflammatory effects in treating pSS.