Molecular Diversity最新文献

Epigenetic regulation intricately governs cellular mechanisms, including proliferation, death, differentiation, and cell cycle orchestration. One such target, Enhancer of zeste homolog 2 (EZH2), is essential for epigenetic regulation. EZH2 trimethylates histone H3 lys27 (H3K27me3), inhibiting target gene transcription and promoting chromatin condensation, thereby initiating tumorigenesis, thus a potentially plausible target to disrupt cancer progression. In this virtual screening study, we utilized two large, open-source natural product libraries, NPASS and LOTUS, to search for potential natural product scaffolds capable of EZH2 inhibition. The merged library was filtered through increasingly rigorous criteria at each stage, including Medchem-based rule filters, 2D Tanimoto similarity, sequential rounds of docking, rescoring via ML-based functions, and binding pose visualization, funneling down to the most promising candidates for further pharmacokinetics and toxicological profiles. The best hits were analyzed for their binding stability through molecular dynamics simulation and their binding free energy estimations. Exploratory chemical analysis was conducted to understand the similarity of hits with known EZH2 chemical space. This comprehensive workflow identified one potential inhibitor, LTS0131784, which exhibited favorable pharmacokinetic toxicity profiling with binding stability and free energy better than the FDA-approved EZH2 inhibitor, Tazemetostat. Furthermore, the plausible binding mechanism was also elucidated by analyzing the per residue-free decomposition of the simulated trajectories, which indicated the involvement of the LTS0131784 with the key residues TYR:111, TRP:521, CYS:560, ASN:585, and SER:561.

This study investigated the molecular targets and pathways modulated by pterostilbene in breast cancer using network pharmacology and in vitro analysis. The structure of chemicals of pterostilbene was retrieved from PubChem, and gene targets were predicted through Swiss Target Prediction. Human-specific targets were validated using UniProtKB and breast cancer-related targets were identified using GeneCards and BioVenn. Protein-protein interaction (PPI) networks were created using STRING and visualized using Cytoscape, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to elucidate biological functions. Molecular docking studies using AutoDock Vina were used to assess the binding interactions of pterostilbene with key nuclear receptors (PTGS2, ESR1, EGFR, and BCL2). Molecular dynamics (MD) simulations over 200 ns in GROMACS confirmed the stability of the ESR1-pterostilbene complex and highlighted significant hydrogen bonding. ADME/T was assessed using the Protox software. In vitro cytotoxicity was assessed using the MTT assay in MCF-7 cells. Sixteen key genes, including PTGS2, ESR1, EGFR, and BCL2, were identified as key targets connecting pterostilbene to breast cancer. PPI analysis identified ESR1, EGFR, and BCL2 as central nodes in the network. Molecular docking revealed robust binding of pterostilbene (below - 8.1 kcal/mol), suggesting potential modulation of estrogen receptor signaling. MD simulations confirmed the stability of the complex with favorable structural dynamics. Toxicity analysis suggested a low risk, and MTT assays revealed selective cytotoxicity of pterostilbene toward MCF-7 breast cancer cells (IC₅₀ = 14.8 µM) with a Selectivity Index of 2.85 compared to normal HEL 299 cells. These findings highlight the potential of pterostilbene as a treatment option for breast cancer, which merits additional exploration in experimental models and human studies.

Thirty-two tetrahydrothiopyran derivatives were synthesized, and their acaricidal activities against Psoroptes cuniculi were evaluated in vitro. The results showed that eight compounds exhibited higher acaricidal activity than ivermectin when evaluated by mass concentration, while six compounds showed superior activity when assessed by molar concentration. Compound b10 showed the lowest LC₅₀ value [62.3 µg/mL (0.12 mM)] and LT₅₀ value (2.2 h at 4.5 mM), far lower than ivermectin [LC₅₀ = 223.3 µg/mL (0.26 mM), LT₅₀ = 8.7 h]. Structure-activity relationship (SAR) analysis showed that the presence of the sulfone structure is crucial for activity, while the types and positions of substituents on the benzene rings are two main factors affecting the activity. Molecular docking results demonstrated that compounds a10, b9, b10 and b11 exhibited good affinity with the AChE protein, along with potential binding modes, suggesting AChE as a promising acaricidal drug target. Overall, these results suggest that tetrahydrothiopyran derivatives, particularly their sulfone derivatives have great potential for the development of novel acaricides.

Vitamin D receptor (VDR) agonists play a pivotal role in modulating immune responses and promoting melanocyte survival, making them potential candidates for vitiligo treatment. The VDR gene is integral to mediating the effects of vitamin D in the immune system, and disruptions in its structure due to missense mutations may significantly contribute to the pathogenesis of vitiligo. Missense single-nucleotide polymorphisms (SNPs) can alter the amino acid sequence of the VDR protein, potentially affecting its ligand-binding affinity and downstream signaling. Investigating these missense SNPs provides critical insights into the genetic underpinnings of vitiligo and may help identify biomarkers for early detection and precision-targeted therapies. This study explored the therapeutic potential of vitamin D analogs in vitiligo management, with a particular focus on their binding interactions and molecular efficacy. Using molecular docking and virtual screening, 24 vitamin D analogs were evaluated. Calcipotriol exhibited the highest binding affinity (-11.4 kcal/mol) and unique interactions with key residues in the VDR ligand-binding domain. Additionally, an analysis of structural variations stemming from missense mutations in the VDR gene highlighted potential impacts on receptor-ligand interactions, further emphasizing the importance of genetic factors in treatment response. These findings underscore the potential of calcipotriol to promote melanogenesis and modulate pigmentation in vitiligo. A comparative analysis identified structural variations influencing the efficacy of other analogs, such as calcitriol and tacalcitol. Although the in silico methods provided valuable insights, the study acknowledges the limitations of excluding dynamic cellular environments and emphasizes the need for experimental validation. Overall, this study enhances our understanding of VDR-targeted therapies, and calcipotriol is a promising candidate for further development in the management of vitiligo.

In previous studies, we discovered YZD-7082B, a selective estrogen receptor degrader (SERD) with excellent comprehensive properties. Here, we reported the development of an efficient multigram-scale synthetic process for YZD-7082 in 13 steps. The route featured a chiral resolution of a thiochroman intermediate with a unique cis-1,2-diaryl motif using a chiral amine and a mild reduction of amide using ZnEt₂/LiCl/(EtO)₃SiH system. This approach also overcomes the issues of high loadings of palladium catalysts and long reaction time. The developed process provided YZD-7082B with an HPLC purity of > 99.8% and ee of > 99%.

Fungal infections are an increasing global health issue. Despite available treatments, fungal resistance reduces medicine effectiveness. This research conducted QSAR analysis on fifty-one 4-aryl-2-hydrazinothiazole derivatives previously evaluated for antifungal activity. The QSAR model was derived from a hybrid method combining genetic algorithms (GA) and multiple linear regression (MLR). The analysis showed a negative correlation between pMIC and RDF100e, ITH, R4m+, RDF120s, and GATS8e. The model was validated using an external test set by the leave-one-out cross-validation method. Additionally, Y-randomization, MAE, and Golbraikh-Tropsha metrics assessed the model's applicability domain. The study offers an in-depth molecular descriptor interpretation through three methods: atomic pair distribution, substructure-based analysis, and molecular surface mapping with cumulative atomic contributions. These methods help identify favorable and unfavorable structural groupings. Key molecular features influencing antifungal activity were identified, particularly the spatial arrangement of N1-hydrazine and C4 fragments in the thiazole nucleus. The research highlights Van der Waals interactions, electronegative atoms in substituents, and electron-donating groups. To address the limitations of modeling a small dataset, we applied the novel ARKA approach-based on Arithmetic Residuals in K-groups Analysis-to reduce descriptor dimensionality while preserving chemical relevance and improving interpretability.

Nocardiosis can lead to disseminated disease and affect various physiological systems, most commonly the skin, lungs, and central nervous system. Nocardia farcinica is unique among other Nocardia species due to its high pathogenicity and antibiotic resistance, and it is more likely to cause brain abscesses and other widespread infections affecting multiple organs. Therefore, new treatment targets are urgently needed to combat the multidrug-resistant nosocomial pathogen N. farcinica. This study aims to prioritize candidate inhibitors using structural bioinformatics and identify prospective therapeutic targets involved in the distinct metabolic pathways of N. farcinica, along with high-throughput virtual screening to identify potential drug compounds. The alpha/beta hydrolase fold domain-containing protein has been identified as a promising target for therapeutic development. Virtual screening of the CMNPD, MNPD, Seaweed, and Specs chemical libraries identified five promising candidates based on their ADME properties and binding affinities. Among these, MNPD738 was inferred as a potent inhibitor due to its stability throughout the molecular dynamics simulation and low binding free energy. These putative therapeutic targets will aid in the development of effective drugs that inhibit the metabolic pathways unique to pathogens. The identified drug targets and lead compounds may contribute to the development of effective therapies for combating drug-resistant N. farcinica infections. Future research should focus on experimental validation of the identified compounds and further exploration of the mechanism underlying N. farcinica pathogenicity.

Focal adhesion kinase 2 (FAK2) is a non-receptor tyrosine kinase that orchestrates key oncogenic processes, including cell adhesion, migration, proliferation, and survival, and is frequently overexpressed in multiple cancer types. Targeting its ATP-binding and active sites has emerged as a promising therapeutic approach. Here, we performed a systematic virtual screening of 11,699 phytoconstituents from the Indian medicinal plants to identify potent FAK2 inhibitors. Docking analysis shortlisted top candidates based on binding affinity, followed by pharmacokinetic profiling (ADMET) and biological activity prediction (PASS). Two compounds, Cucurbitacin S and Kammogenin, exhibited strong binding affinities (- 9.5 and - 9.3 kcal/mol) and favorable ADMET properties, with predicted anticancer and anti-inflammatory activities. Detailed interaction studies revealed stable binding to critical residues, including Asp549 in the active site. Molecular dynamics simulation for 300 ns confirmed the stability and compactness of FAK2-compound complexes, with minimal structural perturbation. Essential dynamics analyses indicated reduced conformational flexibility upon ligand binding, while MM-PBSA calculations demonstrated favorable binding free energies. A comparative analysis with the reference inhibitor PF-562271 indicated the therapeutic potential of both phytochemicals, pending experimental evaluation. These findings suggest that Cucurbitacin S and Kammogenin are promising lead scaffolds for the development of plant-derived FAK2 inhibitors; however, as this is a computational, hypothesis-generating study, the results warrant further experimental validation to confirm their therapeutic potential.

Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase that mediates ESCRT-III disassembly critical for membrane remodeling events like autophagosome closure and endolysosomal repair. Aberrant expression of VPS4 is associated with cancer progression and poor prognosis, making VPS4 a potential anticancer target. To date, very few VPS4 inhibitors have been reported, therefore the identification and development of VPS4 inhibitors is urgently needed. In this study, we employed a multi-tiered structure based virtual screening strategy, molecular dynamic simulation accompanied by pharmacokinetic analysis and in vitro screening to identify novel inhibitors of VPS4. The identified inhibitor comp-23 effectively inhibited the enzymatic activity of VPS4B with an IC₅₀ value of 12.84 ± 2.51 µM. Protein ligand interaction profile and molecular dynamic simulation revealed the ATP binding residues such as Ala137, Gly177, Glu179, Asn279, and His313 were the main contributors to the binding of this compound. Comp-23 serves as a hit compound for further optimization to explore VPS4-related functions.

Natural products are main sources of new chemical entities for pesticide discovery and also important modification substrates for activity enhancement. In this study, a series of novel oleanolic acid derivatives containing piperazine pyrimidine structures were designed and synthesized. Multi NMR and high resolution-mass spectrometry technologies were utilized to characterize the synthesized compounds' structures. Antimicrobial potential of the title compounds was assessed against several phytopathogenic fungi and bacteria, namely Botryosphaeria dothidea, Fusarium sp. in morchella esculenta, Sclerotinia sclerotiorum, Fusarium graminearum, Rhizoctonia solani, Botrytis cinerea in strawberry, Botrytis cinerea in tobacco, Botrytis cinerea in blueberry, Alternaria solani, and Phomopsis sp., and Pseudomonas syringae pv. actinidiae, Xanthomonas oryzae pv. oryzicola, and Xanthomonas axonopodis pv. citri. The results showed that most of these compounds displayed good-to-moderate antimicrobial activities. Among them, compound 4e showed excellent efficacy against B. dothidea with EC₅₀ value of 7.39 μg/mL outperforming pyrimethanil (13.37 μg/mL). In vivo study further confirmed that 4e effectively reduced the incidence of postharvest soft rot in kiwifruit caused by B. dothidea. Mechanistic research revealed that 4e could disrupt cell integrity of B. dothidea causing protein, nucleic acid leakage, and over-generate reactive oxygen species. Furthermore, molecular docking simulation analysis suggested that 4e could readily bound to the isocitrate lyase protein. In addition, compound 4p exhibited promising antibacterial activity superior to the commercial bactericidal thiodiazole copper. The remarkable antimicrobial efficacy of the oleanolic acid derivatives provided great potential for preventing and curing plant diseases.