Chemical Biology & Drug Design最新文献

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.

Our aim is to explore Skullcapflavone II (SFII) function in colorectal cancer and delineate its relevant mechanisms. Malignant behaviors of HCT-116 and SW480 cells were assessed using colony formation, 5-ethynyl-2′-deoxyuridine staining, Annexin V/propidium iodide double staining, scratch and transwell assays. Changes in glycolysis were assessed by seahorse assay and western blot. The potential mechanism by which SFII inhibited the expression of hypoxia-inducible transcription factor-1alpha (HIF-1α) was explored in vitro by molecular docking, surface plasmon resonance, quantitative reverse transcription polymerase chain reaction, western blot, immunofluorescence, cycloheximide chase assay, ubiquitination assay, and some rescue experiments. Besides, a xenograft model was performed to verify SFII function on colorectal cancer. We found that SFII inhibited the malignant behavior and glycolysis of colorectal cancer cells. Furthermore, SFII inhibited HIF-1α protein level in colorectal cancer cells via enhancing its ubiquitination. Moreover, HIF-1α overexpression attenuated SFII effect on the malignant behavior and glycolysis in colorectal cancer cells. In vivo, SFII inhibited tumorigenesis through repressing the HIF-1α-glycolysis pathway in BALB/c nude mice. SFII could suppress proliferation, migration, and invasion in colorectal cancer through inhibiting the HIF-1α-glycolysis pathway.

Dl-3-n-Butylphthalide (NBP) has been reported to relieve neuronal damage by suppressing excessive autophagy. This study explored whether NBP could protect neurons after spinal cord injury (SCI) by inhibiting excessive autophagy, and its intrinsic mechanism were investigated. In methodology, this paper detected the Hippo/YAP pathway activity and autophagy in peripheral blood of SCI patients. A SCI cell model and a rat SCI model were established. Through a series of assays and experimental validation, the effect and mechanism of NBP on neuronal damage after SCI were analyzed. As a result, the activated Hippo pathway, decreased YAP protein, and increased p-YAP, Beclin 1, and LC3 II/I proteins were monitored in peripheral blood of SCI patients. OGD treatment enhanced apoptosis and autophagy, activated the Hippo/YAP pathway, and enhanced YAP nuclear translocation in PC12 cells. NBP treatment eliminated these effects of OGD on PC12 cells. YAP silencing reversed the suppression of NBP on the OGD-induced PC12 cell apoptosis and autophagy. In vivo, the inhibition of NBP on neuronal injury, the Hippo/YAP pathway activity, and autophagy was abolished by YAP silencing. Thus, NBP attenuates autophagy to alleviate neuronal apoptosis after SCI via inactivating the Hippo/YAP pathway. NBP may be useful in SCI treatment clinically.

The kappa opioid receptor (KOR) is one of class A G-protein-coupled receptors (GPCRs), playing important roles in pain sensation. The unique analgesic activity of KOR requires KOR activation that recruits downstream effectors. It is noted that KOR primarily couples to the G_i/o family proteins in the process of KOR signaling that contain the conventional (G_i1, G_i2, G_i3, G_oA, and G_oB) and nonconventional (G_z and G_g) subtypes. The molecular mechanisms governing KOR signaling—particularly its selectivity for G_i/o protein subtypes and the pathway specificity of its ligands—remain unclear. Furthermore, the structural and energetic sequence of events during the activation of KOR and its cognate G_i/o proteins is poorly understood. This lack of knowledge hinders the structure-based design of pharmacophores targeting the KOR/G_i/o complex. It suggests that further research and investigation are required to analyze the crystal structure of the agonists/KOR complexes and various intermediate states in the KOR activation pathway. Some improved enhanced sampling methods, such as umbrella sampling, metadynamics, and Markov State Model methods, can characterize the interaction between GPCRs and different G protein subtypes after specific ligands binding, and the free energy landscapes along the ligand binding pathway. In this review, we discuss the research advances in the molecular mechanisms of KOR signaling. We also present a brief overview of computational conformational sampling methods based on molecular dynamics, including the activation mechanisms, allosteric effects, and actions of biased ligands of GPCRs to describe their activation energy landscape. It can provide an insight into evaluate the convergence of free energy surfaces along coordinates of functional interest, which is helpful to understand the role of GPCR conformational ensembles in intracellular signal transduction.