Journal of Biomolecular Structure & Dynamics最新文献

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.

Cervical cancer burden due to recurrent human papillomavirus (HPV) infections necessitates the urgent need to impede viral proliferation targeting the oncogene E6 of the high-risk serotype HPV16. This study aims to identify a small molecule from a natural product library that could prevent a tumorigenic complex of E6 with p53 in HPV16-positive cervical cancer cells. In silico methods such as high-throughput virtual screening (HTVS) of natural product like library ZINC database followed by atomistic molecular dynamics (MD) simulations were performed to identify lead natural compound. This was validated with in vitro analysis using HPV16 positive SiHa cells and CaSki cells by MTT and flow cytometry assays. Virtual screening identified top 10 compounds with high affinity for HPV16 E6. The docking scores, Protein-Ligand Interaction Profiler analysis, MD simulation and molecular mechanics Poisson Boltzmann surface area-based binding energy estimation narrowed down the search to ZINC1797251, a molecule with stable binding, low energy scores and consistent H-bonds, establishing that it could prevent interaction of p53 and E6. ZINC1797251 inhibited the proliferation of SiHa and CaSki cells with a G_I50 values of 615.40 and 417.30 nM, respectively. The compound reduced HPV16 E6, while increased p53 positive populations in SiHa and CaSki cells. Treatment with ZINC1797251 induced the G₁ cell phase arrest and promoted early and late phase apoptosis in these cells. The restoration of tumor inhibitory activity of p53 in HPV-infected cervical cancer cells to promote apoptosis could be achieved using the ZINC molecule-ZINC1797251. However, further studies are deemed essential for further developments.

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved in this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are reported as promising novel targets in cancer immunotherapy. IDO1 and TDO overexpression in TNBC cells promote resistance to cell death, proliferation, invasion, and metastasis. To date, there are no clinically available small-molecule inhibitors that target these enzymes. Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility. This situation urges the development of a potent drug-like candidate against these key enzymes. A total of 1574 natural compounds were proclaimed and subjected to ADME screening. Subsequently, the resultant compounds were attributed to hierarchical molecular docking and MM-GBSA validation. Ultimately, re-scoring with the aid of combined machine learning algorithms resulted six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among the lead compounds. In addition, the scaffold analysis also highlighted that the chromanone moiety of the hit compound boasts anti-cancer activity against breast cancer cell lines. The reliability of the results was corroborated through a rigorous 100 ns molecular dynamics simulation using the parameters including RMSD, PCA and FEL analysis. In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC.

The escalating incidence of breast cancer globally presents a formidable challenge within oncology. Our research pursued an examination of the anti-cancer potential of Carissa carandas, a shrub traditionally used for medicinal purposes and known for its composition of vital nutrients and phytochemicals. We employed a network pharmacology strategy combined with molecular docking and molecular dynamics simulations to elucidate the intricate relationships between the phytochemical constituents of C. carandas, critical breast cancer proteins, and associated signaling pathways. The study highlighted a complex network of protein interactions, identifying AKT1, HIF1A, PTGS2, and GSK3B as key nodes within this network. These proteins are engaged by numerous investigated compounds from C. carandas and are fundamental in modulating crucial signaling pathways such as those involving Estrogen, HIF-1, Prolactin, VEGF, and Th17 cell differentiation-each of which plays a recognized role in breast cancer progression, affecting tumor growth, proliferation, and metastatic potential. Our analysis suggests that the phytochemicals in C. carandas may exert anti-cancer activity by synergistically modulating these pathways, highlighting the benefit of multi-targeted therapeutic approaches over single-targeted ones. In summary, through the application of advanced network pharmacology, molecular docking, MD simulations, and MM/PBSA analysis, our study offers a detailed exploration of the potential mechanisms by which C. carandas may exert anti-cancer effects. This sets a foundation for further in-depth experimental and clinical trials to validate these mechanisms and support the advancement of novel plant-derived therapeutic options towards breast cancer, with the possibility of significantly advancing the therapeutic options for this prevalent disease.