Journal of Biomolecular Structure & Dynamics最新文献

Triple-negative breast cancer (TNBC), characterized by the absence of Estrogen Receptor (ER), Progesterone Receptor (PR), and amplified HER2, represents an aggressive subtype devoid of targeted therapies, contributing to heightened mortality rates. Matairesinol (MAT) has demonstrated anti-cancer, anti-inflammatory, immunomodulatory, anti-migratory, and antiangiogenic activities. This study investigates MAT's therapeutic potential for TNBC, employing network pharmacology, molecular docking, and molecular dynamics simulations. Through the integration of MAT and TNBC targets from public databases, we identified 47 potential therapeutic targets. Top 10 hub targets, including HIF1A, ESR1, AKT1, EGFR, HSP90AA1, Src, ERBB2, IGF1, ANXA5, and MAPK1, were revealed through protein-protein interaction analysis. Biological enrichments, encompassing GO and KEGG pathway analyses, unveiled insights into functional roles and associated pathways. The Compound-Targets-Pathways-Disease (C-T-P-D) network illustrated relationships between MAT, its targets, and pertinent pathways. Exploring protein-protein interactions with STRING, followed by validation and supplementation using the GeneMANIA-based functional association (GMFA) method and David web wizard, emphasized the MAPK signaling pathway as a more potential target of MAT against TNBC. The biological significance of these findings underscores MAT's potential as a multi-target inhibitor within multiple signaling pathways related to TNBC, showcasing its efficacy against TNBC. Molecular docking and dynamics simulations substantiated the interaction between MAT and the identified hub targets. In conclusion, our in-silico analysis proposes that MAT could mediate a multi-target and multi-pathway anti-TNBC effect with the MAPK pathway as its novel target pathway. These insights into the potential therapeutic mechanisms of MAT offer valuable directions for further research and the development of interventions against TNBC.

Oral squamous cell carcinoma (OSCC), a prevalent form of head and neck cancer, poses a significant health challenge with limited improvements in patient outcomes over the years. Its development is influenced by a complex interplay of genetic alterations and environmental factors. While progress has been made in understanding the molecular mechanisms driving OSCC, pinpointing critical molecular markers and potential drug candidates has proven elusive. This study uniquely endeavors to conduct a meta-analysis to unveil therapeutic genes responsible for OSCC tumorigenesis. A multi-omics approach identified $951$ differentially expressed genes (DEGs) associated with OSCC by analyzing microarray data from the NCBI GEO database. Weighted gene co-expression network analysis (WGCNA) detected a significant hub gene module comprising $805$ genes, followed by the construction of protein-protein interaction network resulting in two small clusters of $7$ gene-encoded proteins each. These clusters were filtered out based on top 10 significant pathways and gene ontology terms to identify six key target proteins with elevated expression levels, acting as potential therapeutic biomarkers for OSCC. Notably, RSAD2 emerged as a novel biomarker linked to OSCC progression. Furthermore, we identified potential inhibitors targeting AURKA, AURKB, and RSAD2 proteins and validated their interactions through molecular dynamics simulation studies. The simulations confirmed the stability of receptor-ligand complexes, suggesting ZINC03839281, ZINC04026167, and ZINC00718292 compounds hold promise as potential inhibitors for therapeutically targeting AURKA, AURKB, and RSAD2 as significant OSCC biomarkers. We recommend further comprehensive studies, including experimental and preclinical investigations, to validate the effectiveness of these lead compounds for OSCC treatment.

1,4-Dialkylamino -5,8-dihydroxy anthraquinones are investigated using density functional theory (DFT) and time-dependent DFT (TD-DFT) for their growth inhibitory potential. The frontier molecular orbital shows that the electron density is located at the anthraquinone core and at the substituents NH and OH in both HOMO as well as in LUMO. The chemical potential and electrophilicity index showed a direct relation, while hardness and hyperhardness had an inverse association with an energy gap. The results of the molecular docking analysis revealed that the anthraquinone molecules have a high affinity for the primary targets of the DNA topoisomerase IIα enzyme. The docking results showed good binding ability with extremely energetically stable scores ranging from -8.9 to -7.6 kcal/mol. Electron correlation descriptors showed a direct link with NLO properties and toxicity.

Pathogenesis and therapeutic drugs for ulcerative colitis (UC) have plagued researchers worldwide. In this study, therapeutic targets, and drugs from Chinese medicines for UC were screened using bioinformatics. We downloaded five datasets from the GEO database and three machine learning algorithms were used for screening diagnostic biomarkers of UC. Combined with the differential genes for UC, gene sets related to bile acid metabolism, short-chain fatty acids, apoptosis, pyroptosis, G-protein-coupled receptors, mitochondria, and autophagy were collected to screen the core targets, and analyze the association of therapeutic genes (diagnostic biomarkers and core targets) with immune cells. In addition, screening ingredients of Chinese medicines based on UC therapeutic targets was performed. Molecular docking, molecular dynamics simulation, and literature validation were also performed. The screening yielded 37 key therapeutic targets, including 5 diagnostic biomarkers (CCL11, CXCL1, PDZK1IP1, TIMP1, and UGT2A3) and 32 core targets based on hot gene sets. Immune cell infiltration was strongly associated with therapeutic targets in UC, especially neutrophils, macrophages, mast cells, and dendritic cells. Furthermore, a total of 33 compounds with high safety had been recognized as having potential to mitigate UC by reverse prediction from Chinese medicines, and molecular docking, molecular dynamics simulation, and literature reports preliminarily validated the screening results. Although further experimental validation is needed, this work provides some potential therapeutic targets and drugs from Chinese medicines against UC.

The development of effective non-nucleoside inhibitors targeting HIV-1 reverse transcriptase (RT) remains a persistent challenge in AIDS research, particularly in overcoming drug-induced mutations. This study focuses on harnessing the potential of Rilpivirine (RPV), a widely recognized non-nucleoside inhibitor, as a foundational structure for designing and synthesizing inhibitors with superior anti-HIV-1 activities compared to RPV. Through strategic conjugation of RPV to molecular umbrellas using diverse linkers such as BSOCOES, DSP, and EGS, a novel series of potent non-nucleoside inhibitors is crafted. Guided by a structure-based drug design approach, this study unveils a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Comprehensive molecular analyses reveal extensive interactions between these NNRTIs and the RT inhibitor-binding pocket, confirming their superior antiviral efficacy against the wild-type virus when compared to RPVs. The innovative strategy employed in this research, focusing on drug-linker-nanocarrier interactions, introduces a promising avenue for designing and developing robust HIV-1 RT inhibitors with potential clinical applications. The findings emphasize the approach's potential for addressing challenges posed by drug-resistant mutations, opening new possibilities for advancing antiretroviral therapy.

Cardiac fibrosis, characterized by excessive extracellular matrix deposition, is a critical contributor to cardiovascular diseases, including heart failure. Transforming growth factor-beta 1 signaling, especially through activin receptor-like kinase 5 (ALK5), plays a key role in cardiac fibroblast activation and fibrosis. Traditional drug discovery approaches face challenges in identifying ALK5 inhibitors. This study leverages computational methods to expedite the discovery of potential ALK5 inhibitors. An active learning model was trained to screen a vast compound library, resulting in the selection of promising candidates. Molecular fingerprint clustering analysis and the absorption, distribution, metabolism, excretion, toxicity evaluation further characterized these compounds. Machine learning-based quantitative structure - activity relationship models predicted their activity. Molecular dynamics simulations assessed binding stability in different environments. DE50349483 and DE21377883 emerged as promising candidates with potential inhibitory effects. This study showcases the power of computational methods in drug discovery, offering hope for innovative therapies in cardiac fibrosis.

The increasing resistance of cancer drugs, especially in the treatment of breast cancer, underlines the urgent need for new and effective cancer drugs. Chemotherapeutic agents based on metal complexes are recognized as highly effective treatment options. The aim of this study is to synthesize a non-platinum chemotherapeutic agent with high efficacy and to investigate its therapeutic effect in mice with tumors. Novel transition metal complexes derived from Schiff base ligands (cobalt(III) H₂salophen complexes) were synthesized, characterized and optimized by quantum calculations based on DFT-D. MDA-MB231 and 4T1 cells were cultured and the scavenging and hemolysis activity, cytotoxic effect, migration and apoptosis were investigated. In addition, the therapeutic effects of the complex were investigated in mice with tumors. The interactions of the target macromolecules were investigated by molecular docking. The results showed that the complexes exhibited considerable cytotoxicity, apoptosis and migration inhibition against tumor cell lines and inhibition of tumor growth in mice, and greatly increased IFN-γ and TNF-α and reduced IL-4 and IL-1β. Data suggest that complex C treatment can enhance immune responses with a Th1 dominance by inducing the secretion of proinflammatory cytokines. Molecular docking experiments confirmed that complex C binds to the most stable state and induces apoptosis by interacting with the DNA minor groove. Our results suggest that complex C triggers apoptosis, leading to a lethal effect on malignant tumor cells, and has the potential to inhibit tumor growth through direct cytotoxic effects. It also stimulates the immune system and alters the cytokine profile.

Breast cancer, the most prevalent cancer in females, is a heterogeneous disease with various molecular subtypes, which presents challenges in diagnosis and treatment. Ubiquitination is one of the most critical post-translational protein modifications, that plays regulatory roles in numerous cellular processes including cell cycle progression, DNA replication & repair, apoptosis, transcription regulation, protein localization, trafficking and signal transduction. This modification can be reversed by deubiquitinases, or DUBs, a superfamily of cysteine proteases and metalloproteases that cleave ubiquitin-protein bonds. Dysregulation of DUBs has been associated to various diseases including cancer, making them promising targets for cancer therapy. We leveraged publicly available breast cancer datasets and employed various bioinformatics tools to identify differentially expressed DUBs in breast cancer. Our analysis identified six genes (COPS5, EIF3H, MINDY1, MINDY2, PSMD14 and USP26) with significant differential expression and survival implications. We further validated our findings experimentally and found upregulation of COPS5, EIF3H and MINDY 1 in MCF-7 and T47D breast cancer cell lines using qPCR analysis. To identify the role of these genes, EIF3H and COPS5, in disease progression, we constructed a protein-protein interaction (PPI) network with genes associated with metastasis and explored their correlation at the gene expression level in breast cancer patients. Together, this comprehensive study sheds light on DUB gene expression patterns in breast cancer with the potential to identify novel targets for therapeutic interventions.

RbgA (ribosome biogenesis GTPase A) is involved in the maturation of later stages of the 50S ribosomal subunit by associating with the 45S ribosomal subunit. However, this binding relies on the specific nucleotide-bound state of RbgA-GTP-bound state is more favorable compared GDP-bound state, attributed to the conformational variations between those states. Therefore, to explore the conformational changes of RbgA, all-atom MD simulations of BsRbgA were carried out under various nucleotide bound states (GDP, GTP, GTP-Mg²⁺ and GMPPNP-Mg²⁺). The analysis of overall conformational changes using RMSD and Rg revealed sharp equilibration for GTP-Mg²⁺ and GMPPNP-Mg²⁺ nucleotide bound systems. Investigating internal variations through RMSF and cluster analyses helps us to identify the functionally important regions and nucleotide driven conformational variations that may stabilize/destabilize the RbgA-ribosome association. In addition, the construction and analyses of the dynamical protein contact network from the simulated trajectory reveal the nucleotide dependent allosteric connections between the nucleotide binding site and the rRNA interacting residues. Furthermore, the visualization followed by the dynamical distance calculations exhibited the possible role of Mg²⁺ in assisting GTP hydrolysis, such as (i) positioning the Asp150 of the switch-I (Sw-I) loop residue in a catalytically feasible configuration and (ii) stabilizing the solvated water molecules at the active-site through Mg²⁺ coordination. The results of our study can be used to design better chemical agents to regulate ribosome biogenesis through modulation of the function of the RbgA.

Phosphodiesterase-5 (PDE5) is a homodimeric enzyme that specifically targets cyclic guanosine monophosphate (cGMP), that mediates many downstream effects such as vasodilation, neurotransmission, and calcium homeostasis. Considering the functions of cGMP, inhibition of PDE5 has been established to have several therapeutic effects in disease conditions such as cancer, cardiovascular diseases and Alzheimer's disease. Consequently, many PDE5 inhibitors were developed but with severe adverse effects such as non-arteritic anterior ischemic optic neuropathy (NAION), priapism, etc. Hence, in our study for the identification of new PDE5 inhibitors from alternative sources, Cassia auriculata L. was identified as a potential PDE5 inhibitors with 56.23% inhibition at 100 μg/mL in vitro. In addition, the respective phytoconstituents were evaluated through molecular docking, interaction studies and MM/GBSA binding free energy calculations, identifying two potential flavone C-glycosides, lucenin-II (-15.977, dG bind = -38.8), stellarin-II (-15.099, dG bind = -34.59), and a flavan derivative (2S)-7,4-dihydroxyflavan(4β-8)-catechin, in comparison to sildenafil (-10.890, dG bind = -75.4) and having frequent contacts with Phe 786, Phe 820, Ser 663, Tyr 664, and other crucial residues at the catalytic site of PDE5. Molecular dynamics simulations performed for 100 ns showed structural stability and compactness of the candidates through RMSD, RMSF which showed less fluctuations. The ADMET analysis revealed favorable pharmacokinetics, and pharmacodynamic properties with no subsequent toxicity in normal cells. The biological target class prediction identified enzymes with similar properties and icariin, which is a well-established natural PDE5 inhibitor was identified as a structurally similar analogue. These findings could lead to the development of novel natural product based PDE5 inhibitors.