Molecular Diversity最新文献

{"title":"Design, synthesis, and in vitro antitumor evaluation of novel benzimidazole acylhydrazone derivatives.","authors":"Lihui Shao, Nianlin Feng, Yue Zhou, Chengpeng Li, Danping Chen, Chenchen Li, Xiang Zhou, Zhurui Li, Zhenchao Wang","doi":"10.1007/s11030-024-11064-8","DOIUrl":"https://doi.org/10.1007/s11030-024-11064-8","url":null,"abstract":"<p><p>This study focuses on the design, synthesis, and evaluation of benzimidazole derivatives for their anti-tumor activity against A549 and PC-3 cells. Initial screening using the MTT assay identified compound 5m as the most potent inhibitor of A549 cells with an IC₅₀ of 7.19 μM, which was superior to the positive agents 5-Fluorouracil and Gefitinib. Cellular mechanism studies elucidated 5m arrests cell cycle at G2/M phase, induces apoptosis along with the decrease of mitochondrial membrane potential and increased reactive oxygen species. Colony formation and wound healing assays demonstrated that 5m markedly inhibited the clonogenic and migratory abilities of A549 cells. Western blot analysis showed an upregulation of pro-apoptotic protein Bax, downregulation of anti-apoptotic protein Bcl-2, and significant downregulation of cell cycle proteins CyclinB1 and CDK-1. These findings suggest that compound 5m effectively suppresses A549 cell proliferation and migration through multiple mechanisms, highlighting its potential as a novel anti-lung cancer agent.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating network pharmacology with molecular docking and dynamics to uncover therapeutic targets and signaling mechanisms of vitamin D3 in Parkinson's disease.","authors":"Cheng Wang, Yi-Ling Wang, Qiu-Han Xu","doi":"10.1007/s11030-024-11090-6","DOIUrl":"https://doi.org/10.1007/s11030-024-11090-6","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural analysis of the impact of germline mutations of p16 in melanoma prone families.","authors":"D Arun, Soumya Lipsa Rath","doi":"10.1007/s11030-024-11089-z","DOIUrl":"https://doi.org/10.1007/s11030-024-11089-z","url":null,"abstract":"<p><p>Cyclin-dependent kinases (CDKs), play essential roles in cell cycle progression. CDK activity is controlled through phosphorylation and inhibition by CDK inhibitors, such as p16. Mutations in p16 can lead to diseases such as cancer. This study examines a series of p16 mutants and their molecular interactions with CDK4 using modelling, molecular dynamics simulations, and docking studies. Despite no significant structural changes in p16 due to mutation, the binding affinity was found to be affected, correlating with conservation scales. Simulations revealed that specific mutations, such as G23D, P114S, and A60V resulted in loss of binding to CDK4, while others like R24Q and G67R showed partial loss. Surface electrostatics emphasised the significance of a positive patch on the binding surface of p16 that faces the CDK4 which was directly impacted due to mutations. Additionally, the partial binding mutants were found to have a lower stability compare to the Wildtype p16/CDK4 complex through the free energy landscape calculations. These findings provide useful insights into the molecular mechanisms by which p16 mutations influence CDK4 binding, potentially informing therapeutic strategies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the molecular mechanism of epimedium herb in treating rheumatoid arthritis through network pharmacology, molecular docking, and experimental validation.","authors":"Chunhui Ding, Qingyang Liu, Xiaohong You, Jianming Yuan, Jinjun Xia, Yuan Tan, Yunxia Hu, Qiubo Wang","doi":"10.1007/s11030-024-11019-z","DOIUrl":"https://doi.org/10.1007/s11030-024-11019-z","url":null,"abstract":"<p><p>This study attempted to explore the molecular mechanism of Epimedium herb (EH) on rheumatoid arthritis (RA) treatment. We employed network pharmacology, molecular docking, and HPLC analysis to investigate the molecular mechanisms underlying the efficacy of EH in treating RA. To assess the efficacy of EH intervention, RA fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) mouse models were utilized. Ultimately, the active compounds icariin, luteolin, quercetin, and kaempferol were identified, with interleukin-1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) emerging as key targets of EH for RA. These targets were found to be downregulated in both in vitro and in vivo experiments following EH intervention. Furthermore, EH treatment induced apoptosis, reduced metastasis and invasion in RA-FLS, and ameliorated arthritis-related symptoms while regulating Th17 and Treg cells in CIA mice.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy.","authors":"Jinglei Xu, Jiahao Yuan, Wenxin Wang, Xiaoning Zhu, Jialong Li, Yule Ma, Shaojie Liu, Jie Feng, Yadong Chen, Tao Lu, Hongmei Li","doi":"10.1007/s11030-024-11045-x","DOIUrl":"https://doi.org/10.1007/s11030-024-11045-x","url":null,"abstract":"<p><p>The p53 protein is regarded as the \"Guardian of the Genome,\" but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GraphkmerDTA: integrating local sequence patterns and topological information for drug-target binding affinity prediction and applications in multi-target anti-Alzheimer's drug discovery.","authors":"Zuolong Zhang, Gang Luo, Yixuan Ma, Zhaoqi Wu, Shuo Peng, Shengbo Chen, Yi Wu","doi":"10.1007/s11030-024-11065-7","DOIUrl":"https://doi.org/10.1007/s11030-024-11065-7","url":null,"abstract":"<p><p>Identifying drug-target binding affinity (DTA) plays a critical role in early-stage drug discovery. Despite the availability of various existing methods, there are still two limitations. Firstly, sequence-based methods often extract features from fixed length protein sequences, requiring truncation or padding, which can result in information loss or the introduction of unwanted noise. Secondly, structure-based methods prioritize extracting topological information but struggle to effectively capture sequence features. To address these challenges, we propose a novel deep learning model named GraphkmerDTA, which integrates Kmer features with structural topology. Specifically, GraphkmerDTA utilizes graph neural networks to extract topological features from both molecules and proteins, while fully connected networks learn local sequence patterns from the Kmer features of proteins. Experimental results indicate that GraphkmerDTA outperforms existing methods on benchmark datasets. Furthermore, a case study on lung cancer demonstrates the effectiveness of GraphkmerDTA, as it successfully identifies seven known EGFR inhibitors from a screening library of over two thousand compounds. To further assess the practical utility of GraphkmerDTA, we integrated it with network pharmacology to investigate the mechanisms underlying the therapeutic effects of Lonicera japonica flower in treating Alzheimer's disease. Through this interdisciplinary approach, three potential compounds were identified and subsequently validated through molecular docking studies. In conclusion, we present not only a novel AI model for the DTA task but also demonstrate its practical application in drug discovery by integrating modern AI approaches with traditional drug discovery methodologies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the binding specificity of interactive compounds targeting ATP-binding cassette subfamily G member 2 (ABCG2).","authors":"Pawan Kumar, Indu Kumari, Rajendra Prasad, Shashikant Ray, Atanu Banerjee, Amresh Prakash","doi":"10.1007/s11030-024-11078-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11078-2","url":null,"abstract":"<p><p>The ATP-binding cassette transporter superfamily plays a pivotal role in cellular detoxification and drug efflux. ATP-binding cassette subfamily G member 2 (ABCG2) referred to as the Breast cancer resistance protein has emerged as a key member involved in multidrug resistance displayed by cancer cells. Understanding the molecular basis of substrate and inhibitor recognition, and binding within the transmembrane domain of ABCG2 is crucial for the development of effective therapeutic strategies. Herein, utilizing state-of-the-art molecular docking algorithms and molecular dynamic (MD) simulations, molecular binding of substrates and inhibitors with ABCG2 are defined, distinctly. We performed extensive virtual screening of Drugbank to identify the potential candidates, and MD simulations of docked complexes were carried out in POPC lipid bilayer. Further, the binding affinities of compounds were estimated by free binding energy employing MM-GBSA. To gain deeper insight into the binding affinities and molecular characteristics contributing to inhibitory potential of certain substrates, we included some well-known inhibitors, like Imatinib, Tariquidar, and Ko 143, in our analysis. Docking results show three compounds, Docetaxel > Tariquidar > Tezacaftor having the highest binding affinities (≤ 12.00 kcal/mol) for ABCG2. Remarkably, MM-GBSA results suggest the most stable binding of Tariquidar with ABCG2 as compared to the other inhibitors. Furthermore, our results suggested that Docetaxel, Ozanimod, Pitavastatin, and Tezacaftor have the strongest affinity for the drug-binding site(s) of ABCG2. These results provide valuable insights into the key residues that may govern substrate/inhibitor recognition, shedding light on the molecular determinants influencing substrate specificity, transport kinetics, and ABCG2-mediated drug efflux.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational screening and molecular dynamics of natural compounds targeting the SH2 domain of STAT3: a multitarget approach using network pharmacology.","authors":"Sachindra Kumar, B Harish Kumar, Raksha Nayak, Samyak Pandey, Nitesh Kumar, K Sreedhara Ranganath Pai","doi":"10.1007/s11030-024-11075-5","DOIUrl":"https://doi.org/10.1007/s11030-024-11075-5","url":null,"abstract":"<p><p>SH2 (Src Homology 2) domains play a crucial role in phosphotyrosine-mediated signaling and have emerged as promising drug targets, particularly in cancer therapy. STAT3 (Signal Transducer and Activator of Transcription 3), which contains an SH2 domain, plays a pivotal role in cancer progression and immune evasion because it facilitates the dimerization of STAT3, which is essential for their activation and subsequent nuclear translocation. SH2 domain-mediated STAT3 inhibition disrupts this binding, reduces phosphorylation of STAT3, and impairs dimerization. This study employed an in silico approach to screen potential natural compounds that could target the SH2 domain of STAT3 and inhibit its function. The phytomolecules (182455) were retrieved from the ZINC 15 database and were docked using various modes like HTVS, SP, and XP. The phytomolecules exhibiting higher binding affinity were selected. MM-GBSA was performed to determine binding free energy, and the QikProp tool was utilized to assess the pharmacokinetic properties of potential hit compounds, narrowing down the list of candidates. Molecular dynamics simulations, thermal MM-GBSA, and WaterMap analysis were performed on compounds that exhibited favorable binding affinities and pharmacokinetic characteristics. Based on docking scores and binding interactions, ZINC255200449, ZINC299817570, ZINC31167114, and ZINC67910988 were identified as potential STAT3 inhibitors. ZINC67910988 demonstrated superior stability in molecular dynamics simulation and WaterMap analysis. Furthermore, DFT was performed to determine energetic and electronic properties, and HOMO and LUMO sites were predicted for electronic structure calculation. Additionally, network pharmacology was performed to map the compounds' interactions within biological networks, highlighting their multitarget potential. Compound-target networks elucidate the relationships between compounds and multiple targets, along with their associated pathways and help to minimize off-target effects. The identified lead compound showed strong potential as a STAT3 inhibitor, warranting further validation through in vitro and in vivo studies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating machine learning and structural dynamics to explore B-cell lymphoma-2 inhibitors for chronic lymphocytic leukemia therapy.","authors":"Rima Bharadwaj, Amer M Alanazi, Vivek Dhar Dwivedi, Sarad Kumar Mishra","doi":"10.1007/s11030-024-11079-1","DOIUrl":"https://doi.org/10.1007/s11030-024-11079-1","url":null,"abstract":"<p><p>Chronic lymphocytic leukemia (CLL) is a malignancy caused by the overexpression of the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), making it a critical therapeutic target. This study integrates computational screening, molecular docking, and molecular dynamics to identify and validate novel BCL-2 inhibitors from the ChEMBL database. Starting with 836 BCL-2 inhibitors, we performed ADME and Lipinski's Rule of Five (RO5) filtering, clustering, maximum common substructure (MCS) analysis, and machine learning models (Random Forest, SVM, and ANN), yielding a refined set of 124 compounds. Among these, 13 compounds within the most common substructure (MCS1) cluster showed promising features and were prioritized. A docking-based re-evaluation highlighted four lead compounds-ChEMBL464268, ChEMBL480009, ChEMBL464440, and ChEMBL518858-exhibiting notable binding affinities. Although a reference molecule outperformed in docking, molecular dynamics (MD), and binding energy analyses, it failed ADME and Lipinski criteria, unlike the selected leads. Further validation through MD simulations and MM/GBSA energy calculations confirmed stable binding interactions for the leads, with ChEMBL464268 showing the highest stability and binding affinity (ΔGtotal = - 80.35 ± 11.51 kcal/mol). Free energy landscape (FEL) analysis revealed stable energy minima for these complexes, underscoring conformational stability. Despite moderate activity (pIC₅₀ values from 4.3 to 5.82), the favorable pharmacokinetic profiles of these compounds position them as promising BCL-2 inhibitor leads, with ChEMBL464268 emerging as the most promising candidate for further CLL therapeutic development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, biological evaluation and molecular docking of novel isatin-oxime ether derivatives as potential IDH1 inhibitors.","authors":"Kangning Wei, Kaige Guo, Ye Tao, Xuanming Gong, Guobing Yan, Liangliang Wang, Ming Guo","doi":"10.1007/s11030-024-11084-4","DOIUrl":"https://doi.org/10.1007/s11030-024-11084-4","url":null,"abstract":"<p><p>A series of novel isatin-oxime ether derivatives were designed, synthesized and characterized by ¹H NMR and ¹³C NMR and HRMS. These compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (A549, HepG2 and Hela) by MTT assay. According to the experimental results, compounds 6a (IC₅₀ = 0.34μM), 6c (IC₅₀ = 14nM) and 6r (IC₅₀ = 45nM) were found as the excellent selectivity and high activity against A549, whereas compounds 6m (IC₅₀ = 12nM) and 6n (IC₅₀ = 25nM) displayed the significant activity for HepG2, respectively. Compound 6f (IC₅₀ = 30nM), 6n (IC₅₀ = 9nM) and 6o (IC₅₀ = 20nM) also showed the excellent activity against Hela. From the experiments of cell migration and colony formation assays, the findings demonstrated that 6m can effectively suppress the migration and growth of HepG2 cells. In addition, the results of molecular docking studies determined the strong binding interactions between the potential active compounds 6m and 6n and the active sites of isocitrate dehydrogenase 1 (IDH1) with the lowest binding affinity energy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142919113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}