Chemical Biology & Drug Design最新文献

The nanocomposites based on aminopropylsilanol (Si~NH₂) and polylysine-anatase (Ans/PL) nanoparticles bearing DNAzymes (Dz) and oligodeoxyribonucleotides (ON) can effectively inhibit the replication of the influenza A/H5N1 virus in cell culture. Nanocomposites based on both types of nanoparticles exhibit high activity. The Dz-containing nanocomposites exhibited higher antiviral activity than those containing ON, reducing influenza A/H5N1 virus production by 3.5 log versus 2.4–3.0 log, respectively. Notably, the effect of Dz incorporated into the nanoparticles was an order of magnitude higher than that of unbound Dz transfected with lipofectamine. Nanocomposites carrying control DNA fragments that are not specific to the influenza A virus genome have practically no antiviral activity, indicating the specificity of the proposed nanocomposites. It was demonstrated that the antiviral efficacy of the nanocomposites is primarily determined by the activity of DNA delivered into cells, which can be varied by altering either the nanocomposite concentration or its capacity for DNA fragments. All of the proposed nanocomposites can be considered as potential antiviral drugs.

In the present study, a series of curcumin analogs (A1–P3) were designed and synthesized for the inhibition of prostate cancer cells by targeting androgen receptor (AR). All synthesized compounds were structurally characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). In vitro cytotoxicity assays demonstrated that multiple compounds exhibited comparable or improved cytotoxicity against AR-positive 22Rv1 cells as compared to dimethylcurcumin (DMC, ASC-J9). Among these compounds, compounds A2, A3, B1–B3, D1, F1, F3, G1, G3, H1, and P3 possessed higher selectivity toward prostate cancer cells as compared to DMC. Compounds O1–O3, A1–A3, B1–B3, F1, F3, G1, I1, and P3 exhibited lower cytotoxicity against AR-negative PC-3 cells than those against 22Rv1 cells. Based on the cytotoxicity results, the structure–activity relationships were analyzed. In the AR protein suppression assay, compounds O1–O3, A1–A3, and I1 exhibited similar inhibitory effects on both full-length AR (AR-FL) and AR splice variant 7 (AR-V7) as compared to DMC, while compound P3 exhibited significantly enhanced AR-FL suppression effect as compared to DMC. In comparison, compounds B2, B3, F1, and F3 exhibited reduced AR-FL and AR-V7 suppression effects as compared to DMC; B1 and G1 exhibited no significant suppression effect on AR-FL and AR-V7, suggesting that these compounds might inhibit prostate cancer cells by multiple mechanisms. Molecular docking simulations further confirmed that compounds O1–O3, A1–A3, I1, and P3 displayed high targeting ability to AR. The probable binding modes of these compounds to AR were also revealed. By modifying the molecular structure of curcumin, this study identified several compounds (A2, A3, P3) with high inhibitory activity and selectivity against castration-resistant prostate cancer cells by targeting AR-FL and AR-V7. These three compounds are promising new candidates for castration-resistant prostate cancer drug discovery.

Ovarian cancer (OC) is one of the most aggressive gynecological malignancies worldwide. The tumor microenvironment and transcriptomic alterations play important roles in OC progression and therapeutic response. Integrative bulk and single-cell transcriptomic analyses may facilitate the identification of prognostic biomarkers and potential therapeutic targets. Multi-Omic datasets from TCGA and GEO were analyzed. Immune-related genes were first integrated with survival information and screened using a random survival forest model to identify five core genes. GO/KEGG analyses were performed on differentially expressed genes, while GSEA and GSVA were used to characterize pathways associated with the core genes. Single-cell RNA-seq data were processed to determine cell-type-specific expression patterns. Molecular docking predicted potential gene-drug interactions. CCK-8, Transwell, and flow cytometry assays assessed the functional role of RELB in OC cells. Five core genes-RELB, CXCL9, PI3, TRAC, and CXCL11-were identified through integration of immune-related genes and random survival forest analysis. Drug sensitivity analysis showed that the expression of all five genes was associated with sensitivity to KU-55933. High expression of key genes was associated with altered immune-related features, while CXCL9, CXCL11, and TRAC were positively associated with CD8+ T-cell abundance and cytolytic activity. Single-cell sequencing identified seven cell types, among which CXCL9 and CXCL11 were highly expressed in monocytes, TRAC in T cells, and PI3 in epithelial cells. Molecular docking predicted a potential interaction between PI3 and 6atu-PROGESTERONE, with a binding energy of −6.35 kcal/mol. RELB was highly expressed in OC cells, and its knockdown significantly inhibited cell proliferation, migration, and invasion while promoting apoptosis. This study identifies a five-gene prognostic signature linked to the immune microenvironment in ovarian cancer. Among them, RELB showed a functional role in OC cell malignant phenotypes, supporting its potential as a biomarker and therapeutic target. Computational drug sensitivity and docking analyses provide hypothesis-generating evidence for potential therapeutic associations that require experimental validation.

Homologous recombination (HR) is an essential pathway for preserving the genomic stability of cells by repairing DNA damage, especially double-strand breaks and interstrand crosslinks. RAD51 recombinase plays a central role in the HR pathway, and when DNA damage occurs, RAD51 binds to single-stranded DNA at the cleavage site to form a helical nucleoprotein filament. Therefore, pharmacological inhibition of RAD51 is emerging as an attractive strategy to block the repair mechanisms of cancer cells and maximize the therapeutic efficacy of conventional radiation and chemotherapy. Several RAD51 small-molecule inhibitors, including CYT-0851, B02, and IBR2, have demonstrated preclinical or early clinical efficacy, but no candidate has yet received regulatory approval. In this study, we identified a novel RAD51 inhibitor from a natural product library using an in silico workflow that combines machine learning models and molecular docking simulations. Among the five machine learning models evaluated, the random forest (RF) model showed the best overall predictive performance after SMOTE-based class balancing and near-zero variance filtering, achieving an accuracy of 0.933, sensitivity of 0.800, specificity of 1.000, Cohen's kappa of 0.842, and ROC-AUC of 0.980. Using an optimized RF model, 1142 natural compounds were virtually screened, and Madecassoside was finally selected by molecular docking analysis. Biological validation showed that MDA-MB-231 cells increased susceptibility to cisplatin after Madecassoside treatment and also markedly inhibited the formation of RAD51 foci induced by cisplatin, strongly inhibiting DNA damage repair. These findings suggest that Madecassoside is a promising RAD51-modulating lead compound that may enhance cisplatin sensitivity by impairing RAD51-mediated DNA repair.

Kcnn4 (KCa3.1) is a calcium-activated potassium channel involved in cell volume regulation and immune cell function, but its role in salivary gland homeostasis remains poorly understood. In this study, we generated constitutive Kcnn4 knockout (Kcnn4^−/−) mice to investigate the impact of Kcnn4 loss on salivary glands and systemic inflammation. Histological examination revealed that Kcnn4^−/− mice had enlarged salivary glands with increased collagen deposition (fibrosis) but no major disorganization on H&E staining. mRNA-seq identified 473 differentially expressed genes (DEGs), with significant enrichment of T- and B-cell-related pathways. Immunofluorescence showed markedly increased infiltration of CD4⁺, CD8⁺ T cells and CD19⁺ B cells into the salivary glands of knockout mice, yet local IgG levels were significantly decreased, which was confirmed by western blotting. Olink proteomic analysis of serum from Kcnn4^−/− mice revealed that among 43 targeted inflammatory proteins, 16 were significantly changed; 15 of these (including Il-6, Tnf, Cxcl1) were decreased, while only Csf1 was increased, indicating a broad systemic anti-inflammatory shift. Collectively, these findings demonstrate that Kcnn4 deficiency induces salivary gland fibrosis, promotes T/B cell infiltration, impairs local antibody production, and suppresses systemic inflammatory mediators, uncovering an unexpected role of Kcnn4 in integrating tissue remodeling and immune function in the salivary gland.

The interaction between c-Myb and the CBP/p300 KIX domain is a key transcriptional event in acute myeloid leukemia (AML) and represents an attractive target for small-molecule intervention. In this study, we applied an integrated computational–experimental strategy to identify new N-aryl anthranilic acid disruptors of the c-Myb–KIX protein–protein interaction. A scaffold-focused library of 3656 N-aryl anthranilic acid derivatives was filtered, docked to the c-Myb-binding groove of KIX (PDB 2AGH), and the top hits were further evaluated by MD simulations, MM/PBSA, FEL, and ADMET analyses. This workflow prioritized four hits (C1–C4) for experimental testing. Computational analyses showed that all four compounds remained bound within the α1/α3 Myb-facing groove, but differed markedly in their predicted effects on the c-Myb–KIX interface. Among them, C3 emerged as the strongest predicted disruptor, whereas C1 was predicted to stabilize the complex. The $��\mathrm{\Delta \Delta }�G_{\mathrm{PPI}}�$ analysis further showed that C3 produced the largest destabilizing effect on the c-Myb–KIX interface (+4.57 kcal/mol), followed by C2 (+2.30 kcal/mol) and C4 (+1.40 kcal/mol), whereas C1 stabilized the complex (−6.47 kcal/mol). These predictions were validated by microscale thermophoresis (MST). The binary c-Myb–KIX interaction showed an apparent K_d of 26.71 ± 0.54 μM, and the compounds inhibited complex formation with IC₅₀ values of 99.6 ± 20.5 μM (C1), 54.7 ± 22.1 μM (C2), 16.5 ± 0.8 μM (C3), and 27.2 ± 2.7 μM (C4). Notably, C3 outperformed the reference inhibitor Naphthol AS-E phosphate (28.8 ± 3.1 μM). Overall, these findings identify C3 as a promising lead and establish N-aryl anthranilic acids as a tractable scaffold for targeting the c-Myb–CBP/p300 KIX interaction.

Pal, R., G. S. P. Matada, G. Teli, et al. 2026. “ Rational Design, Synthesis, Biological Evaluation, and In Silico Study of N-Cinnamamide/Benzamide-(4-(Substituted Phenyl)-6-(4-Cyclohexylphenyl)pyrimidin-2-Yl) Derivatives as EGFR Inhibitors Targeting EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S in NSCLC.” Chemical Biology & Drug Design 108, no. 3: e70390.https://doi.org/10.1111/cbdd.70390.

The article title was incorrect and has been updated from “Rational Design, Synthesis, Biological Evaluation, and In Silico Study of N-Cinnamamide/Benzamide-(4-(Substituted Phenyl)-6-(4-Cyclohexylphenyl)pyrimidin-2-Yl) Derivatives as EGFR Inhibitors Targeting EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S in NSCLC” to “Rational Design, Synthesis, Biological Evaluation, and In Silico Study of N-Cinnamamide/Benzamide-(4-(Substituted Phenyl)-6-(4-Cyclohexylphenyl)pyrimidin-2-yl) Derivatives as EGFR Inhibitors Targeting EGFRWT, EGFRT790M, and EGFRL858R/T790M/C797S in NSCLC.”

The online version of this article has been corrected accordingly.

We apologize for this error.

A new class of pyrimidine nucleoside dimers featuring an ultrashort 1,4-disubstituted 1,2,3-triazole linker was designed and synthesized to explore the biological potential of structurally robust nucleoside analogues as anticancer agents. The target compounds were efficiently obtained via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) from appropriately functionalized 3′-azido- and 4′-ethynyl-5′-deoxy-5′-nor nucleoside precursors and fully characterized by multinuclear 1D/2D NMR spectroscopy and ESI-MS. Their antiproliferative activity was evaluated against a panel of human cancer cell lines comprising cervical (HeLa), breast (T47D), ovarian (SK-OV-3), and glioblastoma (U-138 MG and U-251 MG) cells, with MRC-5 human fibroblasts serving as the control. Several dimers displayed pronounced and cell line-selective antiproliferative activity while exhibiting limited toxicity toward normal cells. Dimers 4, 9, 11, and 17 demonstrated the highest activity against HeLa cells, whereas Dimers 7 and 15 were the most potent against U-251 MG glioblastoma cells, with activities comparable to or exceeding that of 5-fluoro-2′-deoxyuridine (5FdU). Mechanistic studies performed on the most active glioblastoma-directed dimers revealed a concentration-dependent reduction in clonogenic survival and cell migration, accompanied by increased cell death and pronounced S-phase cell cycle arrest, closely resembling the effect of the reference compound 5FdU. In contrast, only a modest and transient increase in intracellular reactive oxygen species (ROS) was detected, indicating that oxidative stress is unlikely to represent the primary mechanism responsible for their antiproliferative activity. Preliminary structure–activity relationship analysis demonstrated that both the nature of the nucleobase and the rigid triazole-linked dimeric architecture substantially influence biological activity and selectivity. Moreover, the synthesized dimers exhibited excellent chemical stability in cell culture medium and human serum, highlighting their exceptional resistance to degradation. Taken together, these findings identify triazole-linked pyrimidine nucleoside dimers as highly stable bioactive scaffolds that inhibit glioblastoma cell proliferation through disruption of DNA synthesis rather than oxidative stress and represent promising candidates for further development as anticancer agents or durable nucleic acid-targeting molecular tools.

Excessive cholesterol contributes to pancreatic β-cell dysfunction and plays a critical role in the pathogenesis of metabolic disorders. FTO is a well-characterized N⁶-methyladenosine (m⁶A) demethylase involved in the regulation of RNA metabolism; however, its role in pancreatic β-cells under cholesterol-induced stress remains poorly understood. The effects of cholesterol on cell viability, apoptosis, pyroptosis, and FTO expression were examined in murine pancreatic BTC6 cells. The functional significance of the FTO–NFATC4 axis was investigated through Fto and Nfatc4 overexpression. RNA sequencing, mRNA stability assays, luciferase reporter assays, and subcellular fractionation analyses were performed to elucidate the underlying regulatory mechanisms. Cholesterol treatment significantly reduced cell viability and promoted apoptosis and pyroptosis in BTC6 cells, accompanied by marked downregulation of FTO expression. RNA-seq analysis identified Nfatc4 as a downstream target of FTO. Mechanistically, Fto overexpression accelerated Nfatc4 mRNA degradation and directly regulated the Nfatc4 3′-UTR, resulting in decreased Nfatc4 expression. Furthermore, Fto overexpression reduced the nuclear accumulation of NFATC4 in cholesterol-treated BTC6 cells. Functionally, forced Nfatc4 expression largely reversed the protective effects of FTO, leading to increased apoptosis and pyroptosis as well as reduced cell viability. FTO protects BTC6 cells against cholesterol-induced injury by suppressing Nfatc4 expression and limiting NFATC4 nuclear accumulation. These findings identify a novel FTO-NFATC4 regulatory axis in pancreatic β-cells and provide new insights into the molecular mechanisms underlying cholesterol-induced β-cell dysfunction, highlighting this pathway as a promising molecular target for the intervention of lipotoxic-mediated pancreatic islet injury.

Latent tuberculosis (TB), caused by dormant, non-replicating Mycobacterium tuberculosis (Mtb), afflicts an estimated 1.7 billion individuals globally and remains a principal barrier to TB eradication. Dormant bacilli are phenotypically tolerant to conventional antibiotics and survive through continued dependence on oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC), making bioenergetic enzymes, including the F1Fo-ATP synthase, cytochrome bcc:aa3 supercomplex, Type II NADH dehydrogenase (NDH-2) and cytochrome bd oxidase, compelling drug targets. This review proposes and rigorously analyses a synergistic, multi-scale computational workflow as a uniquely powerful paradigm for discovering anti-persister agents. The workflow cascades across four integrated stages: (1) dormancy-specific Quantitative Structure–Activity Relationship (QSAR) modelling using hypoxic assay data, with predictive models achieving R² values of 0.83–0.98; (2) rational scaffold design and pharmacophore-guided hit expansion against structurally validated bioenergetic targets, incorporating bioisosteric replacement and fragment merging strategies; (3) structure-based molecular docking exploiting high-resolution cryo-EM structures (resolution ≤ 2.67 Å), with clinically validated inhibitors such as Bedaquiline (BDQ) yielding docking scores of −12.3 to −15.8 kcal/mol; and (4) advanced Molecular Dynamics (MD) simulation under physiologically relevant conditions, including Constant pH MD (CpHMD) at phagosomal pH 4.5 and all-atom mycomembrane models. A critically underexplored dimension, multi-target drug discovery, is systematically examined, focusing on the design of dual-pharmacophore inhibitors that simultaneously engage NDH-2 and cytochrome bd oxidase, thereby raising the genetic barrier to resistance. By framing discovery as a logical progression from statistical correlation (QSAR) through structural hypotheses (scaffold design and docking) to dynamic atomistic validation (MD), this review provides a rigorous, quantitatively grounded computational roadmap for the next generation of anti-persister therapeutics.