Molecular Diversity最新文献

CD47, a cell surface protein, serves as a "don't eat me" signal that prevents immune cells from engulfing healthy cells upon its interaction with SIRPα. Cancer cells exploit this mechanism by overexpressing CD47 to evade immune destruction. Blocking the interaction between CD47 and its receptor, SIRPα, is a promising therapeutic strategy. Targeting the interactions between these surface proteins with small molecules is quite challenging, and on the other hand, antibodies offer potential. However, the interactions between antigen (CD47) and antibody (B6H12.2) play a crucial role in this scenario, and increasing the affinity by mutating the interacting residues might impact the inclination and effectiveness of the antibody towards antigen. Thus, this study focuses on designing antibodies with increased affinity and stability towards the antigen compared to the wild-type. Residual scanning calculations were performed to mutate the interacting as well as the hydrophobic residues of the antibody and affinity was assessed. Computational approaches, including antigen-antibody docking studies and molecular dynamics simulations, were employed to evaluate the affinity, stability and therapeutic potential of these modified antibodies.

In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC₅₀ values of 180.7, 190.3 and 215.8, 218.6 μg/mL, respectively, surpassing the efficacy of NingNanmycin, which exhibited EC₅₀ values of 284.1 and 247.1 μg/mL. The preliminary mechanistic studies indicated that H6 and Y5 had ahigh binding affinity for the tobacco mosaic virus capsid protein (TMV-CP), potentially obstructing the self-assembly and replication processes of TMV particles. Furthermore, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. H6 has the potential to be developed as a novel antiviral.

Adenosine receptors (A₁, A_2a, A_2b, A₃) play critical roles in cellular signaling and are implicated in various physiological and pathological processes, including inflammations and cancer. The main aim of this research was to investigate structure-activity relationships (SAR) to derive models that describe the selectivity and activity of inhibitors targeting Adenosine receptors. Structural information for 16,312 inhibitors was collected from BindingDB and analyzed using machine learning methods. 450 molecular descriptors were calculated for each molecule and compounds were classified based on their activity levels and therapeutic targets. The variable importance in projection (VIP) algorithm identified key discriminating features. Classification models were built using supervised Kohonen networks (SKN) and counter-propagation artificial neural networks (CPANN) algorithms. Model validity was assessed via cross-validation, applicability domain analysis, and test sets. These models were then used to screen a random subset of 2 million molecules from the ZINC database. Three descriptors-hydrophilic factor (Hy), ratio of multiple path count over path count (PCR), and asphericity (ASP)-were identified as critical for discriminating active and inactive inhibitors. SKN models exhibited high sensitivity (0.88-0.99) and yielded an average area under the curve (AUC) of 0.922 for virtual screening. This study aimed to enhance the development of highly selective Adenosine receptor ligands for diverse therapeutic applications by identifying critical molecular features specific to each isoform.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, often linked to overexpression or abnormal activation of the epidermal growth factor receptor (EGFR). The issue of developing resistance to third-generation EGFR kinase inhibitors, such as osimertinib, underscores the urgent need for new therapies to overcome this resistance. Our findings revealed that compound A8 exhibits 88.01% kinase inhibition efficacy against the EGFR^L858R/T790M mutation at a concentration of 0.1 μM, with an IC₅₀ value of 5.0 nM. Moreover, its selectivity for this double mutation is 29.5, surpassing that of osimertinib. Most notably, A8 demonstrates an inhibitory activity of 2.9 nM against the EGFR^{L858R/T790M/C797S} triple mutation, outperforming the benchmark drug osimertinib. Furthermore, compound A8 has demonstrated strong antiproliferative effects against H1975 cells, and its activity was better than osimertinib. The mechanism by which compound A8 operates as a selective EGFR^L858R/T790M inhibitor was confirmed through a series of cell migration, apoptosis, and cell cycle assays. This lays the foundation for the development of a new structural type of EGFR kinase inhibitors.

Succinate dehydrogenase (SDH) has been identified as one of the ideal targets for the development of novel nematicides. However, the resistance of nematodes to fluopyram, one of the commercialized SDH inhibitors, is becoming a growing concern. Since expanding the structural diversity around an active scaffold is a useful strategy for drug development, herein a series of fluopyram analogues with a broad, biologically relevant indole moiety were synthesized and evaluated for nematicidal activity against C. elegans. Fifty-six novel target compounds were synthesized and characterized by ¹H NMR, ¹³C NMR, and HRMS. The bioscreen results revealed that a few compounds such as C16 and D21 with LC_50/72 h values of 8.65 mg/L and 6.83 mg/L, respectively, showed compatible activity to that of the commercial nematicide tioxazafen (LC_50/72 h = 5.98 mg/L). Molecular docking indicated that these compounds could effectively bind to the active site of SDH by forming hydrogen bonds with Trp215 and Tyr96, and causing a cation-π interaction with Arg74. The work suggests that indole-containing derivatives may represent a promising template for the development of new nematicides.

This study focuses on the design, synthesis, and evaluation of benzimidazole derivatives for their anti-tumor activity against A549 and PC-3 cells. Initial screening using the MTT assay identified compound 5m as the most potent inhibitor of A549 cells with an IC₅₀ of 7.19 μM, which was superior to the positive agents 5-Fluorouracil and Gefitinib. Cellular mechanism studies elucidated 5m arrests cell cycle at G2/M phase, induces apoptosis along with the decrease of mitochondrial membrane potential and increased reactive oxygen species. Colony formation and wound healing assays demonstrated that 5m markedly inhibited the clonogenic and migratory abilities of A549 cells. Western blot analysis showed an upregulation of pro-apoptotic protein Bax, downregulation of anti-apoptotic protein Bcl-2, and significant downregulation of cell cycle proteins CyclinB1 and CDK-1. These findings suggest that compound 5m effectively suppresses A549 cell proliferation and migration through multiple mechanisms, highlighting its potential as a novel anti-lung cancer agent.

Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.

Cyclin-dependent kinases (CDKs), play essential roles in cell cycle progression. CDK activity is controlled through phosphorylation and inhibition by CDK inhibitors, such as p16. Mutations in p16 can lead to diseases such as cancer. This study examines a series of p16 mutants and their molecular interactions with CDK4 using modelling, molecular dynamics simulations, and docking studies. Despite no significant structural changes in p16 due to mutation, the binding affinity was found to be affected, correlating with conservation scales. Simulations revealed that specific mutations, such as G23D, P114S, and A60V resulted in loss of binding to CDK4, while others like R24Q and G67R showed partial loss. Surface electrostatics emphasised the significance of a positive patch on the binding surface of p16 that faces the CDK4 which was directly impacted due to mutations. Additionally, the partial binding mutants were found to have a lower stability compare to the Wildtype p16/CDK4 complex through the free energy landscape calculations. These findings provide useful insights into the molecular mechanisms by which p16 mutations influence CDK4 binding, potentially informing therapeutic strategies.

This study attempted to explore the molecular mechanism of Epimedium herb (EH) on rheumatoid arthritis (RA) treatment. We employed network pharmacology, molecular docking, and HPLC analysis to investigate the molecular mechanisms underlying the efficacy of EH in treating RA. To assess the efficacy of EH intervention, RA fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) mouse models were utilized. Ultimately, the active compounds icariin, luteolin, quercetin, and kaempferol were identified, with interleukin-1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) emerging as key targets of EH for RA. These targets were found to be downregulated in both in vitro and in vivo experiments following EH intervention. Furthermore, EH treatment induced apoptosis, reduced metastasis and invasion in RA-FLS, and ameliorated arthritis-related symptoms while regulating Th17 and Treg cells in CIA mice.

The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.