Chemical Biology & Drug Design最新文献

Nitric oxide (NO) was previously thought to have a beneficial role in hair growth, but it is unclear whether NO donors can encourage hair development. Therefore, this study aims to systematically investigate the physiological mechanisms underlying the therapeutic effects of NO donors in alopecia. We first screened the chemical targets of seven types of NO donors from DrugBank and SwissTargetPrediction, and further identified the differentially expressed genes (DEGs) of three types of alopecia from the GEO database. Integrated bioinformatic analysis was subsequently performed to comprehensively reveal potential pathways. A total of 339 chemical targets of NO donors were collected and 237, 266, and 1158 DEGs of androgenic alopecia (AGA), alopecia areata (AA) and central centrifugal cicatricial alopecia (CCCA) were identified in this study. We further extracted 20 CCCA-related targets from the intersection of 339 targets and 1158 DEGs of CCCA for the following analysis. Through integrative analysis, we found that hesperidin (HP) may exert dual regulatory effects on apoptosis and senescence pathways in hair follicle cells through its specific interactions with BCL2, MAPK8, MMP13 and AURKB, effectively mitigating hair loss. Overall, our work elucidates the molecular mechanisms of NO donors-mediated hair follicle protection, which could pave the way for future investigations into NO-based interventions and their potential clinical applications.

The SARS-CoV-2 nonstructural protein 15 (Nsp15) is an endoribonuclease that plays a critical role in viral replication and immune evasion through its NendoU domain. The unique enzymatic mechanism of Nsp15 has attracted considerable attention as a potential therapeutic target, and the identification of its inhibitors could facilitate the development of novel antiviral agents against coronaviruses. Although biochemical and structural studies have provided important insights into Nsp15 function, no comprehensive review has yet focused on computational approaches applied to the discovery of Nsp15 inhibitors. Consequently, this study aims to address this gap by summarizing recent in silico research focused on the structure, function, and inhibition of Nsp15. Special attention is given to inhibitors derived from both natural and synthetic sources, as well as their binding interactions and predicted pharmacological potential. By integrating current computational findings, this review highlights novel prospects for the rational design of Nsp15-targeted therapeutics to combat SARS-CoV-2 and other related pathogenic coronaviruses.

Ulcerative colitis (UC), a chronic inflammatory bowel disorder with no clear etiology, causes diverse complications and severely impairs patients' quality of life. Lipocalin-2 (LCN2) is recognized as a potential fecal biomarker for UC. Brusatol (BR), a quassinoid compound isolated from Brucea javanica, has exhibited anti-inflammatory and therapeutic effects in preclinical studies. While BR inhibits UC progression, its specific molecular mechanisms remain to be elucidated. An in vitro cell model of UC was constructed by treating human normal colorectal mucosal cells (FHC) with tumor necrosis factor-alpha (TNF-α). Cell viability and apoptosis were assessed using CCK-8, 5-ethynyl-2′-deoxyuridine (EdU) and flow cytometry. Additionally, inflammatory cytokines and ferroptosis-related factors were analyzed using corresponding kits. Western blot and qRT-PCR were conducted for protein and mRNA detection. Bioinformatics analysis and co-immunoprecipitation (Co-IP) assay were employed to investigate the relationship between LCN2 and ubiquitin protein ligase E3A (UBE3A). Finally, in vivo UC models were established, followed by BR treatment and evaluation of colon pathological changes and target molecule expression. In the TNF-α-induced FHC cell injury model, BR significantly suppressed cell injury and ferroptosis, and this effect was associated with downregulating LCN2 expression. The ubiquitin ligase UBE3A negatively regulated LCN2 expression. The protective effect of UBE3A overexpression against TNF-α-induced damage was abolished by LCN2 upregulation. BR alleviated cell injury by upregulating UBE3A expression, which in turn inhibited LCN2 expression. In the UC mouse model, BR mitigated colonic pathological damage, downregulated LCN2 expression, and upregulated UBE3A levels. BR exerted anti-colitis effects by upregulating the expression of UBE3A and downregulating LCN2 levels, thereby inhibiting cell injury, ferroptosis, and colonic pathological damage.

Thanks to their DNA-crosslinking methods, platinum-based chemotherapeutics—which were first introduced by the coincidental discovery of cisplatin in 1965—have long been a mainstay of cancer treatment, with notable effectiveness in treating colorectal, ovarian, and testicular cancers. In order to address the enduring problems of toxicity, resistance, and restricted selectivity, this study charts their development from the traditional agents cisplatin, carboplatin, and oxaliplatin to next-generation developments. Classical mechanisms, rooted in aquation and apoptotic induction, are now complemented by emerging targets, including RNA, mitochondria, and protein–protein interactions, alongside novel cell death pathways like ferroptosis. Nonclassical complexes, such as Pt(IV) prodrugs and multinuclear agents, enhance delivery and overcome resistance, while synergistic strategies with immunotherapy (e.g., PD-1 inhibitors), nanoparticle delivery, and radiotherapy amplify efficacy. Precision medicine advances patient stratification via genomic (e.g., TP53 and BRCA) and proteomic biomarkers, liquid biopsies for real-time monitoring, and pharmacogenomics to adapt dosing. Sustainability initiatives, stable formulations, affordable generics, and green synthesis guarantee worldwide access, especially in low-resource environments. Recent trials have validated the use of hypoxia-activated prodrugs, AI-driven predictive models, and DNA repair inhibitors (e.g., NER and PARP) in the fight against resistance. Looking forward, integration with CRISPR, 3D tumor modeling, and epigenetic targeting heralds a new frontier, supported by interdisciplinary collaboration bridging chemistry, biology, and technology. This convergence of foundational principles and cutting-edge innovations positions platinum therapy for a transformative era, promising enhanced precision, efficacy, and equity in cancer care worldwide.

A novel series of covalent pyrrolo[2,3-d]pyrimidine cinnamamides was synthesized and evaluated for anticancer activity. The compounds were tested against three cancer cell lines—MDA-MB-231 (triple-negative breast cancer), A549 (non-small cell lung cancer), and U-87 MG (glioblastoma), alongside a cytotoxicity assessment on non-tumor NIH/3 T3 mouse embryonic fibroblast cell line. Compound 5k (IC₅₀ = 0.99 ± 0.45 μM) and 5i (IC₅₀ = 1.15 ± 0.14 μM) demonstrated markedly higher potency against MDA-MB-231 cells compared to cisplatin (IC₅₀ = 34.36 ± 0.16 μM), whereas 5e was found active against A549 cells (IC₅₀ = 1.41 ± 1.13 μM). None of the active compounds exhibited significant toxicity against normal NIH/3 T3 cells. Molecular docking studies involving covalent modification at the ATP-binding sites of EGFR (L858R/T790M), HER2, and JAK3 via key interactions with Cys797 (EGFR/HER2) and Cys909 (JAK3) supported their irreversible mechanism of action. Glutathione-binding assay confirmed the covalent adduct formation with a prominent molecular ion peak corresponding to the adduct. Density Functional Theory analyses of the leading compounds revealed low HOMO-LUMO energy gaps, which correlated with elevated electronic reactivity and biological capability. Electrostatic surface potential maps further highlighted distinct electrophilic character around the acrylamide warhead, facilitating potential covalent bond formation with nucleophilic Cys residues in the target proteins. In silico ADMET profiling confirmed favorable drug-likeness and safety attributes. Together, these findings support the discovery of this novel class of covalent pyrrolo[2,3-d] pyrimidine cinnamamides as promising and safer lead candidates for anticancer therapy, particularly against triple-negative breast cancer.

Glioma, a prevalent malignancy globally, presents a serious threat to human health. Recent research has highlighted the significant anti-tumor properties of 6-gingerol (6-G), an active component of the traditional Chinese medicine ginger, though its precise mechanisms in glioma remain to be fully elucidated. This study employed network pharmacology, molecular docking, and dynamic simulation to explore the targets and underlying mechanisms of 6-G's anti-glioma effects, followed by in vitro validation of the key pathways. Drug-related targets were identified via PharmMapper and Swiss target prediction databases, while disease-related targets were sourced from GeneCards, OMIM, and TTD. The intersection of these datasets yielded potential therapeutic targets. Subsequent PPI network analysis using STRING11.5 and core gene screening with Cytoscape 3.9.1 led to the construction of a “drug-target network” and the identification of central genes. GO and KEGG enrichment analyses were conducted on potential therapeutic targets. Molecular docking and dynamic simulations were utilized to analyze the interactions between core genes and 6-G. Ultimately, the primary mechanism underlying 6-G's anti-GC effects was validated through in vitro experiments. A total of 183 potential targets for 6-G treatment of glioma were identified, with PPI analysis and core target screening revealing 10 critical targets. Enrichment analyses underscored the PI3K/AKT pathway as the primary signaling mechanism through which 6-G exerts its therapeutic effects. Molecular docking results showed that AKT1, HSP90AA1, EGFR, and MAPK3 were the key targets of 6-G in the treatment of glioma, and dynamic simulations further verified these findings. In vitro findings demonstrated that 6-G effectively inhibits the proliferation of U87 and U251 glioma cells, induces apoptosis, arrests the G1 phase of the cell cycle, and suppresses migration and invasion. Western blot analysis confirmed a significant downregulation of p-AKT in the PI3K/AKT pathway. In conclusion, 6-G impairs glioma cell proliferation, promotes apoptosis, induces G1 phase arrest, and inhibits migration and invasion, primarily through the suppression of the PI3K-AKT pathway. This finding provides a robust foundation for further research and clinical application.

Quinazolin-4-one scaffolds offer rich anticancer chemistry but often trade potency for selectivity. Building on a tubulin-targeting lead (MJ-65), 12 new derivatives (26–37) were synthesized to dissect geometry–activity relationships and enhance the polarity of C2-substituents. Cytotoxicity was profiled against cancerous (HCT116 and CAL27) and normal (FHC) cells. In silico studies employed CDOCKER against tubulin (PDB 5NJH), GROMACS for molecular dynamics (MD), and ProTox-3.0 for toxicity estimation. The previously synthesized geometry-matched pairs 21–25 were active at 10 μM. In contrast, their isomers 26–30 were largely inactive, revealing a configuration-dependent binding mechanism. Optimizing polarity yielded Holu-7 (compound 35; 2,4-dihydroxyphenyl at the C2-position), which exhibited sub-50 nM IC₅₀ in HCT116/CAL27 cells and > 10 μM in FHC cells and induced robust G₂/M arrest. Docking/MD supported stable vinca-site engagement, with hydrogen bonds to ASP179/ASN206 and π-stacking with TYR224. ProTox-3.0 predicted a higher LD₅₀ and absence of major organ toxicities relative to MJ-65. This data indicates that configuration-aware, polarity-tuned design can deliver selective quinazolinone anticancer candidates; therefore, Holu-7 merits further preclinical evaluation.

Coronavirus Disease-2019 (COVID-19) caused by SARS-CoV-2 remains a serious health concern worldwide. Inhibitors of the protein–protein interaction (iPPI) between the SARS-CoV-2 spike protein (S) and human Angiotensin-Converting Enzyme-2 (ACE2) are promising as potential antiviral agents. This study aimed to identify and evaluate novel compounds as inhibitors of the S receptor-binding domain (RBD) and ACE2 interaction through Eugenol- and Structure-Based virtual screening approaches. The hit compounds were corroborated as protein–protein interaction inhibitors using an ELISA-based enzyme assay. Molecular docking and molecular dynamics (MD) studies of the selected compounds showed that they maintained a molecular interaction and stability (RMSD fluctuations less than 4 Å) with essential residues of the S protein. The best compound, Eu-1 (IC₅₀ = 16 μM), prevented the interaction between the S protein and ACE2 receptor efficiently with an 83.7% inhibition at 50 μM. In addition, Eu-1 had an adequate value of cytotoxicity (CC₅₀ > 200 μM). Therefore, Eu-1 is a candidate compound for further SARS-CoV-2 preclinical experiments.