Molecular Diversity最新文献

Antifungal peptides (AFPs) are natural defense molecules that inhibit fungal pathogens, protecting against external fungal invasion. Their mechanism of action can effectively combat fungal resistance, offering broad-spectrum efficacy, high safety, and other advantages. However, traditional laboratory methods for identifying AFPs are inefficient and expensive. Consequently, with the development of artificial intelligence, computational models for identifying and predicting AFPs have emerged. But existing methods often rely on datasets compiled from literature and inadequately consider AFP representation, such as ignoring spatial features. Furthermore, single Graph neural Networks (GNNs) can suffer from feature bias in capturing features. To this end, this study constructed a state-of-the-art and comprehensive dataset and developed a deep learning model, AFP-GFuse, that integrates sequence and structural information and three complementary GNNs. A hierarchical cross-attention mechanism is designed to dynamically align and fuse multi-graph feature representations. Experiments demonstrate that AFP-GFuse outperforms state-of-the-art models in predicting AFPs, achieving an accuracy of 0.9140. Ablation experiments further validate the effectiveness of structural representation. Furthermore, comparisons with three individual GNNs demonstrate that integrating a cross-attention mechanism effectively complements their representational limitations and improves overall model performance. To facilitate broader application, we also provide open data 8.4and an online service, AFP-GFuse, publicly available at http://www.bioai-lab.com/AFP-GFuse .

STING (stimulator of interferon genes) is an endoplasmic reticulum-resident membrane-spanning protein that is widely expressed in mammalian cells and functions as a central regulator for the innate immunity. Aberrant activation of the STING axis due to loss-of-function or gain-of-function mutation leads to various autoimmune and autoinflammatory disorders such as Aicardi-Goutières syndrome, systemic lupus erythematosus, and STING-associated vasculopathy with onset in infancy. Here we report the design, synthesis, and structure-activity relationship (SAR) of the isoindoline-2(1H)-carboxamide STING inhibitors. SAR study allowed us to identify compound 3b as a potent STING inhibitor with human- and mouse-STING inhibitory IC₅₀ values of 6.2 and 12.5 nM, respectively. It also markedly suppressed the activation of the STING pathway in both human and murine cells. Furthermore, compound 3b exhibited preferable in vivo protective efficacy against cisplatin-induced acute kidney injury.

Breast cancer represents the most prevalent malignancy worldwide and persists as the principal contributor to cancer mortality in women. Natural origins supply invaluable bioactive constituents demonstrating potential antitumor properties with improved safety. In this investigation, a sequence of alepterolic acid derivatives bearing indole or indazole functionality coupled with piperazine substituents were conceived and synthesized. Validation of molecular structures employed ESI-MS, ¹H NMR, and ¹³C NMR spectroscopic techniques. Experimental outcomes established that derivatives 14n and 14t manifested IC₅₀ readings of 4.29 ± 0.25 µM and 4.15 ± 0.01 µM, correspondingly, in MCF-7 cellular models. Extended evaluations disclosed that both derivatives provoked morphological modifications and restrained proliferative capacity following concentration- and duration-based patterns. Western blot demonstrated that exposure to compound 14t evoked substantial upregulation of critical apoptosis indicators-specifically activated caspases 9, 8, 6 and cleaved PARP-concomitant with an elevated Bax/Bcl-2 ratio within MCF-7 cell populations. Treatment with 14t additionally instigated mitochondrial anomalies, characterized by marked depolarization of mitochondrial transmembrane potential and augmented reactive oxygen species (ROS) generation. Furthermore, administration of 14n enhanced concentrations of activated caspase 8, caspase 6, and cleaved PARP in MCF-7 cells. These observations imply that apoptosis induction by 14t in MCF-7 systems operates through dual intrinsic and extrinsic cascades, whereas 14n principally initiates apoptotic mechanisms via the extrinsic route. Conclusively, integration of indole-piperazine moieties into alepterolic acid scaffolds constitutes a viable tactical framework for generating innovative therapeutic candidates.

A novel and environmentally benign electrochemical method has been developed for the regioselective C6 thiocyanation of tetrahydroquinolines using potassium thiocyanate (KSCN) as an inexpensive and readily available thiocyano source. This transition-metal-free and oxidant-free protocol proceeds under mild conditions, enabling efficient construction of C(sp²)-SCN bonds. Utilizing TEMPO as a redox mediator, the reaction affords 6-thiocyanato-tetrahydroquinoline derivatives in moderate to good yields. The protocol is also applicable to the C4 thiocyanation of anilines and the C6 selenocyanation of tetrahydroquinolines. The method demonstrates excellent regioselectivity, high atom economy, broad substrate scope, and good functional group compatibility, providing a practical approach to a range of valuable thiocyanated and selenocyanated derivatives.

Cellulase enzymes comprising endo-1,4-β-glucanase, exo-1,4-β-glucanase, and β-glucosidase mediate the degradation of cellulosic biomass and are frequently used in biofuel production from lignocellulose. β-glucosidases that convert cellobiose to glucose are sensitive to temperature and glucose concentration and thus often show limited catalytic efficiency. Several β-glucosidases having high temperature or glucose tolerance have been evaluated, but a potential candidate having high efficiency along with thermostability and glucose tolerance is yet to be identified. The present study focuses on marine metagenome investigation for the identification of high-potential β-glucosidase. Nine β-glucosidases of the GH 1 family having (β/α)₈ barrel domains were observed. Six β-glucosidases were predicted to have a Tm value higher than 65 ℃, including ECV39653.1 β-glucosidase. Molecular docking of all identified β-glucosidases with cellobiose and glucose revealed that ECV39653.1 β-glucosidase has the highest negative binding energy of - 7.4 kcal/mol for cellobiose at the active site, while having insignificant binding of glucose with binding energy of -5.4 kcal/mol at a site different from the active site. The structural analysis showed an effective similarity of ECV39653.1 β-glucosidase with known thermostable and glucose-tolerant β-glucosidases. The prediction of kinetic parameters gave k_cat/K_m value of 989.08163 sec^-1 mM^-1 for cellobiose. In-depth MD simulation and free binding energy analysis showed highly effective binding of cellobiose over the 100 ns trajectory with an average total binding energy of - 17.45 kcal/mol. The PCA and analysis of free energy landscape showed less variance and conformational changes in ECV39653.1 β-glucosidase cellobiose complex form in comparison to apo-form and disclosed attainment of global minima, thus proving the high ECV39653.1 β-glucosidase-cellobiose complex stability. The analysis of the simulation trajectory revealed that glucose left the binding cavity during simulation, thus disclosing weak binding and, hence, effective glucose tolerance. Therefore, the present in-silico investigation provides a promising high-efficiency, thermostable, and glucose-tolerant ECV39653.1 β-glucosidase. Further studies can provide scope for its utilization in the development of effective technologies for large-scale biofuel production.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive impairment. It seriously affects the health and quality of life of the elderly. It has a complex pathogenesis including β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, cholinergic neurotransmitter deficiency, metal ion dyshomeostasis, and oxidative stress, etc. Despite intensive research, there is still a lack of effective clinical drugs to treat or control AD progression. Natural products and their derivatives exhibit multi-target anti-AD effects, together with low toxicity and affordability, have emerged as promising lead compounds for drug discovery. This review summarizes the studies on anti-AD activities of natural products bearing γ-pyranone structure and their derivatives, and further discusses their structure-activity relationships (SARs), which provided a theoretical basis for the development of effective anti-AD drugs.

A series of flavonol derivatives containing benzothiazole were designed and synthesized. The structures of all the compounds were characterized by NMR and HRMS. The results of the activity assay showed that some of the target compounds possessed outstanding in vivo antiviral activity against the tobacco mosaic virus (TMV). Among them, the median effective concentration (EC₅₀) of L20 was 90.5 and 202.2 μg/mL for curative and protective activity against TMV, respectively, which was better than that of ningnanmycin (NNM: 252.0 and 204.2 μg/mL). The results of microcalorimetric thermophoresis (MST) and molecular docking experiments indicate that L20 binds TMV-CP more strongly than NNM; density functional theory (DFT) calculation the indicating that L20 is more chemical reactivity than NNM. In addition, malondialdehyde (MDA) and superoxide dismutase assay (SOD) activity measurements also fully confirmed that L20 stimulated the plant immune system and strengthened the plant's resistance to diseases by lowering the MDA content and increasing the SOD activity. Furthermore, the chlorophyll content test experiment found that L20 could reduce the destructive effect of viruses on chloroplasts, increase the content of chlorophyll, and promote photosynthesis. In conclusion, above experimental results suggested that flavonol derivatives containing benzothiazole could be further investigated as new plant virus antiviral drugs.

The p53 Y220C mutation, a prevalent structural variant in human cancers, compromises DNA binding and tumor suppressor functions by destabilizing the protein structure. Leveraging a combined approach of structure-based virtual screening, molecular dynamics simulations, and in vitro assays, we have identified C8, a racemic compound with an indole core and α, β-unsaturated carbonyl groups, as a covalent stabilizer for p53 Y220C. Protein thermal shift and homogeneous time-resolved fluorescence assays confirmed that C8 and its analogs selectively bind to p53 Y220C and restore its DNA binding ability. Subsequent molecular dynamics simulations and structure-activity relationship analyses showed that both enantiomers of C8 form covalent bonds with Cys124 and Cys220, stabilizing the mutant structure. C8 and its analogs emerge as promising lead candidates for restoring the Y220C mutant's transcriptional function, highlights the potential of this scaffold for further optimization into p53 Y220C-targeted therapeutics.