Molecular Diversity最新文献

Presented herein is a fundamentally new organophosphine-mediated annulation paradigm that converts benzo[c][1,2]dithiol-3-ones and iso(thio)cyanates into pharmacologically relevant 1,3-benzothiazin-4-one architectures through an unconventional S to C-N atom exchange process. Distinct from conventional cyclization approaches, this metal-free strategy offers exceptional advantages including: broad substrate scope (45 examples, up to 96% yield), simple operation (ambient temperature, open flask), mild reaction conditions and exceptional utility in late-stage functionalization of bioactive molecules. Comprehensive mechanistic analysis uncovered a phosphine-mediated S-S bond activation followed by formal [4 + 2] cyclization.

Escitalopram, a selective serotonin reuptake inhibitor (SSRI), treats depression and related anxiety symptoms by enhancing the physiological effects of serotonin (5-HT). This study explored the potential drug-drug interactions (DDIs) of combining escitalopram with flavonoid compounds (kaempferol and quercetin). The inhibitory effects of flavonoids on escitalopram metabolism were studied using human liver microsomes (HLM), rat liver microsomes (RLM) and Sprague-Dawley rats. The concentration of escitalopram and its metabolites were detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our findings revealed that the half-maximal inhibitory concentration (IC₅₀) of kaempferol against escitalopram in HLM and RLM were 14.34 and 8.69 μM, respectively, and both were mixed inhibitory mechanisms, consisting of competitive and non-competitive inhibition in HLM and non-competitive and un-competitive inhibition in RLM, respectively. Moreover, the IC₅₀ of quercetin against escitalopram in HLM and RLM were 11.25 and 8.14 μM, respectively, and the inhibitory mechanisms were both mixed inhibitory mechanisms consisting of non-competitive and un-competitive inhibition. The in vivo results showed that quercetin significantly increased the AUC_(0-t), AUC_(0-∞) and C_max of escitalopram by 0.91-, 0.90- and 1.83-fold, respectively, while kaempferol and quercetin significantly reduced the CL_z/F by 41.3% and 44.7%, respectively. In addition, kaempferol reduced the C_max of N-desmethyl escitalopram by 62.1%. Therefore, the inhibitory effects of kaempferol and quercetin on the metabolism of escitalopram carries the risk of causing DDI and requires caution in combination.

A hormonal disorder that severely affects women's routine physical and emotional life is PCOS (Polycystic Ovary Syndrome). It has been witnessed as a heavily detrimental and most threatening disorder, causing multiple complications, such as type 2 diabetes, cardiovascular disease, and endometrial carcinoma. One of the major causes of PCOS is hyperandrogenism, which results in the dysfunction of the ovaries. The enzyme responsible for such excessive production of androgen is 3-beta hydroxysteroid dehydrogenase-1 (3βHSD1), which is an oxidoreductase that performs multiple functions in steroid metabolism. Trilostane and troglitazone are proposed inhibitors for 3βHSD1 with anticipated side effects. With the aim to identify non-steroidal phytocompounds, structure-based ligand screening against ChEBI was done, which resulted in 3459 compounds. Initially, NAD was docked into the protein to have an active enzyme structure. Then other ligands were docked. Based on a docking score of - 8.0 kcal/mol, ADME properties, and interaction profiling, seven compounds-Aphidicolin, Sagequinone methide A, Premarrubiin, Hoda acetal, Ophiopogonanone A, Brosimacutin C, and Cremastranone-were listed out. All these seven compounds were reported with medicinal importance in the literature. Hence, the stability of protein-ligand complexes was analyzed in detail through 200 ns MD simulation. Results from this study establish these compounds as leads for drug development to combat PCOS.

We have recently demonstrated that 7-O-methylpunctatin (MP), a novel homoisoflavonoid, suppresses inflammation-induced arterial pathogenesis. However, the precise biochemical mechanisms underlying its atheroprotective effects remain elusive. In this study, we employed various in silico studies to elucidate MP's plausible potential and the specific molecular pathways through which it exerts its influence on atherosclerosis. Our analysis of MP's pharmacokinetic, physicochemical, and toxicological properties revealed a profile characterized by favorable absorption, efficient metabolism and excretion, and minimal toxicity. Through target identification and protein-protein interaction analyses, we identified ALOX5 as a pivotal hub gene-an enzyme critically involved in the pathogenesis of atherosclerosis. Furthermore, we identified ten transcription factors and four kinases as potential targets. Molecular mechanics/generalized-born surface area calculations, complemented by time-scale molecular dynamics simulations, revealed that MP binds to ALOX5 with high affinity, modulating its structural stability, rigidity, compactness, overall folding pattern, and residual correlations and motions. These findings corroborate previous in vitro and in vivo investigations that underscore the anti-atherosclerotic effects of ALOX5 inhibition, thereby positioning MP as a promising therapeutic candidate for combating atherosclerosis.

This study integrates transcriptomic, proteomic, and immunoinformatic analyses to identify peptide-based and repurposed drug candidates for Breast cancer therapy. Differential gene expression profiling across four independent datasets (GSE134938, GSE213481, GSE214054, and GSE148657) identified 455 significantly upregulated and 439 downregulated genes out of 6,124, with ANKFY1 (GSE134938) and ATE1 (GSE148657) emerging as robust markers. Functional clustering highlighted consistent upregulation of genes involved in extracellular matrix (ECM) remodeling, tumor invasion, and metabolic reprogramming (COL1A1, FN1, SPP1, MMPs, SCD), alongside downregulation of adhesion and mitochondrial genes, suggesting epithelial-mesenchymal transition (EMT) and metabolic vulnerabilities. Protein-protein interaction network analysis revealed ANKFY1, STARD4/5, and CADM1 as central hubs enriched in lipid metabolism, ECM regulation, and cytoskeletal signaling. Functional enrichment underscored cholesterol transport, steroid biosynthesis, and PPAR/AMPK signaling as key pathways in BC pathogenesis. Proteomic profiling of 21 breast cancer-associated proteins generated 28,732 human-specific peptides, prioritized using a composite scoring system integrating immunogenicity, physicochemical traits, and safety. Top peptides, including SCAMP2, CADM1, and FNBP1, exhibited high MHC binding affinity (IC50 < 30 nM), non-allergenic and non-toxic profiles, and favorable solubility, with motif analysis identifying conserved functional patterns across SCAMP2, CADM1, and FNBP1. Structural modeling and virtual screening validated these proteins as tractable targets, with nilotinib and tucatinib emerging as promising multitarget repurposed drug candidates. At the same time, terfenadine displayed strong binding but cardiotoxic potential. Collectively, these results highlight lipid-driven oncogenesis and ECM remodeling as central to BC biology and provide a translational framework for peptide-based immunotherapy and drug repurposing.

Magnolol, a bioactive principle from Magnolia officinalis, has demonstrated potential anticancer properties. This study investigates the anticancer effects of magnolol on liver cancer cells under in vitro conditions, expounding its molecular mechanisms, target interactions, and therapeutic potential. SwissADME evaluated drug-like physicochemical properties of magnolol while as SwissTargetPrediction, SuperPred, and GeneCards identified potential biological targets of magnolol and disease targets (liver cancer) respectively. Protein-protein interaction (PPI) networks were generated by using STRING database and Cytoscape software with identification of hub genes by using Cytohubba plugin. Functional enrichment analysis, such as gene ontology (GO) and KEGG pathway analyses of the common biological targets was performed in order to identify main biological processes, molecular functions, cellular components and signalling pathways. Hub genes were differentially expressed, staged, and prognosed using GEPIA2. Using CB-Dock2, binding affinities of magnolol with NFKB1, EGFR, and ERBB2 were examined, while MD simulations was performed using Desmond Software. MTT, clonogenic, Transwell, EDU, and flow cytometry assays were implemented to evaluate the therapeutic efficacy of magnolol on HepG2 cell proliferation, cellular morphology, cell migration, DNA synthesis, and cellular apoptosis. Magnolol demonstrated favorable drug-like physicochemical properties, including high GI absorption and BBB permeability. A total of 44 overlapping targets between magnolol and liver cancer were identified, forming a dense PPI network with 10 hub genes, including NFKB1, EGFR, and ERBB2. GO and KEGG analyses revealed enrichment in critical pathways such as PI3K-Akt, MAPK, and ErbB signaling, emphasizing the potential of magnolol in cancer treatment. Hub gene analysis showed differential expression patterns, with NFKB1 and ERBB2 overexpressed in tumors, correlating with advanced stages and poor survival, while EGFR downregulation indicated a favorable prognosis. Docking studies revealed strong binding affinities, particularly for ERBB2 (Vina score - 10.1), with MD simulations confirming stable interactions. Functional assays in HepG2 cells demonstrated dose-dependent inhibition of proliferation, colony formation, migration, and DNA synthesis, alongside significant apoptosis induction. This study highlights magnolol as a possible lead molecule candidate for liver cancer, targeting key molecular pathways and hub genes associated with disease progression. Its ability to modulate critical cellular functions and induce apoptosis, coupled with its strong binding affinity and stability with pivotal proteins, underscores its therapeutic potential.

A deformylation-driven multicomponent reaction to access Hantzsch-type pyridine was first realized via a domino Michael/retro-Michael/Aldol/deformylation cascade. This operationally simple protocol fulfills green chemistry principles by employing readily available feedstocks in neat water under metal-free conditions. Mechanistic investigations establish deformylation of 3-formylchromones is the pivotal activation step, enabling the domino pathway toward pyridines while circumventing energy-intensive decarboxylation. Unprecedented in scope, the strategy accommodates diverse electrophiles and functionalized chromones, achieving 58-85% yields. This rationally designed deformylation cascade provides a sustainable blueprint for synthesizing medicinally important heterocycles without transition-metal contamination.

Ceramides, central bioactive mediators of sphingolipid metabolism, critically regulate signal transduction and essential cellular processes. Among six ceramide synthases (CERS1-6), CERS2 preferentially synthesizes very-long-chain ceramides (>C22-24) and holds exceptional promise as a pharmacological target for modulating ceramide levels and composition, with therapeutic potential in metabolic disorders, neurodegenerative diseases, and cardiovascular pathologies. Inhibitors specifically targeting CERS2 remain an urgent unmet need for targeted therapeutics modulating ceramide subclasses. In this study, we firstly performed a multi-step virtual screen of over 10 million drug-like compounds from the ZINC20 database to identify hits against CERS2. Compounds were hierarchically ranked by Glide HTVS/SP/XP docking scores (thresholds: - 6.5/ - 7.0/ - 7.5 kcal/mol), MM-GBSA binding free energies, and ligand-based clustering. Next, the top two candidates were selected for molecular dynamics (MD) simulations, which revealed that Hit-325144 formed highly stable interactions with key catalytic residues His212 and His213 in the CERS2 active site, indicating strong binding affinity. Finally, experimental validation employing LC-MS/MS-based ceramide quantification and fluorescence-coupled enzymatic assays using recombinant human CERS2 protein confirmed Hit-325144's dose-dependent inhibition of CERS2 activity. This study establishes a high-throughput, cost-effective virtual screening framework for CERS2 inhibitor discovery and provides a structurally validated lead compound Hit-325144 as a foundation for developing small-molecule therapeutics targeting CERS2-mediated ceramide dysregulation in associated diseases.