Molecular Diversity最新文献

Molecular docking is a routine and essential procedure in computational drug discovery. However, it is well known that current techniques are still far from perfect, especially when being applied to molecular fragments. In this work, we combined advantages of traditional energy-based docking, a diffusion model, intermolecular interaction filters, and ML-assisted scoring function to achieve higher accuracy. We compiled a comprehensive dataset of molecular fragments to evaluate our new protocol - HybriDock - in comparison with three other docking algorithms including DiffDock, Matcha and AutoDock Vina. HybriDock demonstrated remarkable improvements over these methods, highlighting the advantage of combining modern molecular modeling approaches. Additionally, we analyzed the influence of fragment chemical properties and protein family on the ability to predict accurate binding modes and highlighted up-to-date limitations and future directions.

To develop novel functional molecules with both antifungal and antitumor activities, this study rationally designed and synthesized 11 acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives based on the bioactive fragment characteristics of isoxazoline, acridine, tetrahydronaphthalene, and spirocycle moieties. Using o-aminoacetophenone and other reagents as starting materials, the target compounds were prepared via a multi-step synthetic route involving copper-catalyzed Ullmann coupling, Wittig reaction, and Huisgen cycloaddition. The results of biological activity assays demonstrated that these compounds exerted definite antifungal effects against a variety of fungi, especially Ampelomyces humuli. Among them, compound 10a displayed the half-maximal effective concentration value of 0.9768 µg/mL against Ampelomyces humuli, which was superior to that of the positive controls Chlorothalonil (1.767 µg/mL), Famoxadone (13.87 µg/mL), and Carbendazim (27.02 µg/mL). The mycelial growth rate method indicated that its inhibitory effect on the mycelial growth of Ampelomyces humuli was concentration-dependent. Fluorescence staining experiments revealed that this compound could induce damage to fungal cell membranes and inhibit fungal spore secretion. In vitro experiments confirmed that it possessed certain protective and curative effects on corn leaves infected by Ampelomyces humuli. In addition, cytotoxicity studies showed that these compounds exhibited relatively high toxicity against normal cells while exerting significant antiproliferative activity against human colorectal cancer cells; notably, compound 10e had the half-maximal inhibitory concentration value of 2.53 µM, which was higher than that of the positive controls Cisplatin (36.00 µM) and Doxorubicin (10.43 µM). These findings suggest that the novel acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives with multiple active fragments hold promise as candidates for the development of new antifungal agents and antitumor drugs.

Polyethylene terephthalate microplastics (PET-MPs) function as endocrine-disrupting agents that interfere with steroidogenesis and folliculogenesis, potentially contributing to polycystic ovary syndrome (PCOS). This study integrates computational toxicology and machine learning to delineate the mechanisms linking PET-MP exposure to PCOS pathogenesis. We conducted systematic multi-omics analysis by merging PET-MP-associated targets from ChemBL, PubChem, SwissTargetPrediction, SuperPred, and GeneCards with PCOS-related genes from GeneCards and the Comparative Toxicogenomics Database. Differential expression and weighted gene co-expression network analysis (WGCNA) were then applied to ovarian transcriptome datasets (GSE106724 and GSE137684). LASSO regression was used to prioritize hub genes, which underwent validation via diagnostic nomograms, molecular docking, molecular dynamics simulations, single-cell expression analysis, immune microenvironment profiling, and pathway enrichment. The results identified 22 overlapping genes connecting PET-MP exposure to PCOS, with RAB9A and MAOB highlighted as potential diagnostic biomarkers that appear to influence inflammatory responses, disrupt steroid hormone homeostasis, and induce mitochondrial dysfunction. Single-cell analysis revealed hub gene enrichment in ovarian granulosa cells (GCs), indicating targeted impacts on the follicular microenvironment, while immune profiling showed macrophage and γδ T cells as possible mediators of PET-MP-induced PCOS. Molecular docking and dynamics simulations demonstrated stable binding affinities of PET-MPs to RAB9A and MAOB. Overall, these findings position RAB9A and MAOB as environmental susceptibility biomarkers associating PET-MP exposure with PCOS development, providing molecular insights for targeted interventions.

The construction of quaternary carbon centers at the para-position of benzamide derivatives is of significant importance for the synthesis of pharmaceutical agents and their key precursors. Such structural motifs can serve directly as small-molecule targeted compounds or be further elaborated into complex ligand architectures to meet diverse pharmacological requirements. However, achieving high selectivity in the formation of these quaternary carbon centers remains a long-standing challenge. We herein report a method for the para-selective construction of quaternary carbon centers on benzamide derivatives via iron catalysis. This transformation proceeds at room temperature using benzamide derivatives and tertiary alkyl Grignard reagents. By employing a catalytic system comprising inexpensive iron(II) salt and tert-butylmagnesium chloride, this method enables the introduction of sterically demanding tertiary alkyl groups at the para-position with high regioselectivity, effectively suppressing common side reactions such as alkyl group isomerization or ortho-alkylation. This approach exhibits a diverse range of applicable aryl amides, though N-alkyl substrates are not tolerated.

ATP-citrate lyase (ACLY) is an upstream enzyme involved in fatty acid synthesis, cholesterol metabolism, and histone acetylation. Therefore, selective inhibition of ACLY represents a promising strategy for the treatment of dyslipidemia and various cancers. Recently, the cryo-EM structure of the ACLY complex with the allosteric inhibitor NDI-091143 has been reported, providing an opportunity to discover new potent inhibitors of this emerging target. In this in silico study, we report structure-based models that were rigorously developed and evaluated using reported allosteric inhibitors of ACLY. The pharmacophore model (ROC-AUC = 0.85, GH = 0.78, and EF_1% = 49.18) and the molecular docking model (RMSD_redock = 0.884 Å and ROC-AUC = 0.95) were applied to virtual screening of the ZINC15 library. During hit selection for further evaluation by molecular dynamics simulations, post-docking analysis was performed based on docking scores (ΔG_dock) alone and in combination with the Tanimoto similarity coefficient of protein-ligand interaction fingerprints (Tc_IFP). The combined ΔG_dock and Tc_IFP approach enabled the identification of four out of five selected top hits with binding free energies more favorable than that of the reference compound NDI-091143, supporting their potential as allosteric ACLY inhibitors. These compounds may be subjected to further experimental evaluation to confirm their biological activity. In addition, the workflow developed in the present study may provide a basis for future discovery and optimization of allosteric ACLY inhibitors.

Liver fibrosis is a progressive disease caused by chronic inflammation and the activation of hepatic stellate cells (HSCs). This disease manifests as the abnormal proliferation and migration of HSCs, as well as the excessive deposition of the extracellular matrix. Chalcone analogues exhibit various biological activities, including anti-inflammatory, anti-proliferative, and apoptotic modulation properties, making them promising candidates for anti-fibrotic drug development. To enhance anti-fibrotic activities and decrease their side-effects, 31 novel chalcone derivatives were synthesized and evaluated. Among all the compounds, c31 exhibited the strongest anti-inflammatory activity, and its IC₅₀ is 3.05 ± 0.12 µM; and it effectively inhibited the activation and proliferation of HSC-T6 cells. Mechanistic studies revealed that c31 inhibits HSC activation by downregulating the expression levels of inflammatory factors, such as TNF-α, IL-6, and IL-1β, and by interfering with NF-κB and JNK signaling pathways. Additionally, c31 inhibited HSC-T6 proliferation and promoted apoptosis by blocking a G2/M phase cell cycle; and it also significantly inhibited HSC-T6 cell migration. In a rat model of CCl₄-induced liver fibrosis, c31 improved pathological symptoms, decreasing collagen deposition, fibrotic protein expression, and ALT and AST levels. Meanwhile, it also reduced the secretion of inflammatory factors, thereby alleviating CCl₄-induced liver fibrosis. In summary, c31 had significant anti-inflammatory and anti-fibrotic effects in both in vivo and in vitro; this indicates c31 has the potential to be used as a therapeutic candidate for hepatic inflammation and fibrosis.

An efficient protocol for the synthesis of aryl thiocyanates from anilines and KSCN by merging nitrate reduction with copper-catalysis has been developed. The combination of inexpensive Fe(NO₃)₃·9H₂O and Na₂S₂O₃·5H₂O enabled a safe and green diazotization of anilines. The fleeting diazonium salts reacted with KSCN rapidly to afford the aryl thiocyanates in good to excellent yields using Cu(OTf)₂ as the catalyst. The operational simplicity and safety, good substrate scope and scalability highlight the synthetic significance of this protocol.