Molecular Diversity最新文献

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.

Designing peptide binders is a widely used strategy for developing potential therapeutic agents. Fibroblast Growth Factor 7 (FGF7) plays a critical role in cell proliferation and tissue repair, and its dysregulation is associated with various diseases. Here, we established an integrated computational-experimental workflow to identify peptide inhibitors targeting FGF7. We first generated a library of 100,000 random 8-mer peptides and progressively narrowed it using peptide toxicity analysis and binder prediction via PepBind-SVM. These methods eliminated 75.8% of non-viable candidates, enabling rapid library refinement. Next, we applied a sequence-based machine learning approach incorporating principal component analysis to classify the remaining peptides. The random candidates from three identical cluster were selected and subjected to molecular docking using Rosetta FlexPepDock. Peptides with the highest predicted binding affinity were synthesized and experimentally validated using isothermal titration calorimetry (ITC). Eight peptides demonstrated measurable binding to recombinant human FGF7 (rhFGF7), with three peptides exhibiting notably higher affinities of 43-67 µM. While these affinities are relatively weak and may limit immediate biological relevance, they nevertheless confirm binding and highlight both the potential and current limitations of the pipeline. Further molecular dynamics simulations revealed that key FGF7 residues, including R65, R67, and N149 play significant roles in stabilizing peptide interactions. This study presents an integrated in silico-to-in vitro pipeline for identifying preliminary peptide binders of FGF7 and provides mechanistic insights that may inform subsequent optimization and rational peptide design.

The coexistence of altered or overexpressed penicillin-binding protein 3 (PBP3) and β-lactamases has led to a significant decrease in treatment success rates of Klebsiella pneumoniae. Targeting both proteins simultaneously could offer a robust strategy to overcome resistance in K. pneumoniae. Herein, a curated library of 147,953 terpenoids-renowned for their structural diversity and multi-targeting potential against bacterial pathways-was screened via structure-based pharmacophore modelling and molecular docking. Five terpenoids with higher binding tendencies for K. pneumoniae PBP3 and KPC-2 beta-lactamase were identified. These leads exhibited favourable pharmacokinetic, drug-likeness, and low toxicity profiles. The most promising leads (TP93780 and TP156670) demonstrated superior binding free energies (BFE) against K. pneumoniae PBP3 (- 24.40 ± 5.20 and - 23.46 ± 3.50 kcal/mol) and KPC-2 beta-lactamase (- 15.38 ± 4.09 and - 16.83 ± 3.75 kcal/mol) when compared to ceftaroline (- 21.82 ± 8.64 kcal/mol) and clavulanate (- 10.85 ± 34.40 kcal/mol), respectively. The energetics revealed that the promising leads were driven by balanced hydrophobic and moderate electrostatic interactions, compared to the polar-dominated binding profile of the reference standards. The post-molecular dynamics structural analysis revealed an enhanced overall stability of the TP93780 and TP156670 bound structures. The principal component analysis and free energy landscape analyses revealed more constrained and localised motions in the bound structures compared to the unbound structures and reference standard bound complexes. The favourable molecular orbital energies and the thermodynamically stable terpenoid-bound structures underpin their potential as dual modulators of K. pneumoniae PBP3 and KPC-2 beta-lactamase. Further in vitro studies are underway.

The re-emergence of monkeypox virus (MPXV), renamed mpox, as a global health emergency in 2022 has intensified the search for robust therapeutic interventions. This review summarizes the virological, structural, and pharmacological dimensions of MPXV, with a focus on the virus's lifecycle from host cell entry to dissemination. MPXV's double-stranded DNA genome exhibits clade-specific plasticity, with variations in genes like OPG065 and MOPICE driving virulence, immune evasion, and host adaptation. Key viral proteins, including entry facilitators A27L and L1R, envelope protein F13L (VP37), and immune modulators such as B19R and C12L, serve as critical targets for antiviral strategies. Structural insights from cryo-EM and X-ray crystallography reveal conserved motifs across orthopoxviruses, enabling pan-orthopox drug design. Current therapeutics, such as tecovirimat (targeting VP37 to block egress), brincidofovir, and cidofovir (inhibiting DNA polymerase E9L), offer symptomatic relief but face hurdles like resistance mutations (e.g., A314V in E9L) and suboptimal efficacy in immunocompromised patients. Emerging resistance underscores the need for vigilant genomic surveillance. Novel modalities, including monoclonal antibodies against antigenic proteins like A35R and M1R, cytokine-based immunotherapies, and host-directed agents modulating autophagy or interferon pathways, show promise. Computational approaches integrating AI-driven screening, molecular dynamics simulations, and multi-omics have pinpointed repurposed candidates like lumacaftor and conivaptan as VP37 inhibitors. This integrative framework advocates for combination therapies, personalized regimens based on clade profiling, and global collaboration to mitigate MPXV's adaptive potential. By bridging virology and pharmacology, the review charts pathways for innovative drug development to combat this zoonotic threat effectively.