Molecular Diversity最新文献

{"title":"Correction: Addressing the selectivity challenge in matrix metalloproteinases: fragment-based design of MMP-9 inhibitors targeting the S1' pocket.","authors":"Ashish Kumar, Md Sameer, Arbaz Sujat Shaikh, Yaman Chauhan, Venkata Rao Kaki","doi":"10.1007/s11030-026-11735-8","DOIUrl":"https://doi.org/10.1007/s11030-026-11735-8","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164015","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":"Subtractive proteomics-driven identification of AgrA and structure-guided discovery of phytochemical and marine natural products as novel anti-quorum sensing therapeutic leads against Enterococcus faecium.","authors":"Pradeep Kumar Sriram, Manikandan Jayaraman, Maharaja Muthuvairam Subbulakshmi, Shaslinah Nathar, Dhamodharan Prabhu, Jeyakanthan Jeyaraman","doi":"10.1007/s11030-026-11539-w","DOIUrl":"10.1007/s11030-026-11539-w","url":null,"abstract":"<p><p>Enterococcus faecium, a member of the ESKAPE pathogens, has become a significant clinical threat due to its rapidly increasing resistance to frontline antibiotics. This gram-positive bacterium has developed multidrug resistance through prolonged exposure to hospital environments, posing serious risks to immunocompromised patients. The present study aimed to identify novel therapeutic targets from the E. faecium genome and to explore the potential of marine natural products as anti-quorum sensing agents. A comprehensive subtractive proteomics pipeline incorporating non-human homology, essentiality, subcellular localization, druggability, and pathway uniqueness identified the accessory gene regulator A protein (AgrA) as a key target involved in quorum sensing, biofilm formation, and virulence. Following structural quality assessment, a hierarchy-based virtual screening of MNPs from the CMNPD and SPECS natural product libraries was carried out to identify potential AgrA inhibitors. The virtual screening workflow shortlisted three promising MNPs (CMNPD6428, CMNPD30814, and SPECS AE-765) with favourable binding affinities and pharmacokinetic properties. Docking scores ranged from - 7.46 to - 8.01 kcal/mol, and MM/GBSA binding free energy calculations (≤ - 50 kcal/mol) further supported their strong interactions. Pharmacokinetic evaluation indicated acceptable safety profiles. Density functional theory analysis confirmed the chemical stability and reactivity of the compounds through HOMO-LUMO energy gap assessment. Finally, 500 ns molecular dynamics simulations and principal component analysis-based free energy landscape mapping validated the structural stability and sustained binding of the identified MNPs within the AgrA binding pocket. Overall, this study highlights three promising MNPs as potential anti-quorum sensing leads against E. faecium, offering a foundation for future therapeutic development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7967-7991"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759277","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 characteristics and SARs of EZH2 inhibitors.","authors":"Ruosong Qin, Baohong Ma, Shuo Mou, Mengwen Yuan, Jiahe Xing, Jiwei Shen, Shi Ding, Ye Chen, Ju Liu","doi":"10.1007/s11030-025-11272-w","DOIUrl":"10.1007/s11030-025-11272-w","url":null,"abstract":"<p><p>Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a central role in the post-translational methylation of histone H3 lysine 27 (H3K27me3), thereby regulating gene silencing. Extensive studies have demonstrated that EZH2 is frequently overexpressed in a broad range of malignancies, where it promotes tumorigenesis and progression. Elevated EZH2 expression is strongly associated with increased tumor cell proliferation, invasion, metastasis, therapeutic resistance, higher tumor grade, and poor clinical outcomes. Currently, two EZH2 inhibitors have received regulatory approval for the treatment of cancers such as lymphoma, and both have shown clinical benefit in patients with relapsed or refractory disease. In this review, we provided a systematic analysis of recent advances in EZH2 inhibitor development, with a particular emphasis on classification based on core structural scaffolds. We highlighted the structure-activity relationships (SARs), pharmacological profiles, and the respective advantages and limitations of representative compounds in preclinical development. These insights were intended to offer the design of next-generation EZH2 inhibitors with improved selectivity, safety, and translational potential for targeted cancer therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6499-6529"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537706","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":"In silico discovery of natural and synthetic inhibitors targeting AKT1 in prostate cancer.","authors":"Hemantha Mani Kumar Chakravarthi Chanda, Sudheer Kumar Katari","doi":"10.1007/s11030-026-11563-w","DOIUrl":"10.1007/s11030-026-11563-w","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8061-8085"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759347","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":"Identification and validation of natural product-based KRAS^G12D inhibitors through structure-based virtual screening, molecular dynamics simulation, and in vitro studies.","authors":"Divya Pandey, Shubham Dwivedi, Kuldeep K Roy","doi":"10.1007/s11030-026-11554-x","DOIUrl":"10.1007/s11030-026-11554-x","url":null,"abstract":"<p><p>KRAS^G12D is a common cancer-driving mutation that fuels the progression of several aggressive cancers, particularly pancreatic, colorectal, and lung cancers. Despite its well-established role in tumor development, effective therapeutic options that directly target KRAS^G12D remain limited. In this study, a structure-based virtual screening strategy was employed to identify potential KRAS^G12D inhibitors. Molecular docking was used to screen a library of traditional Chinese medicine (TCM) compounds, followed by ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling. The top five drug-like candidates were subjected to 200 ns molecular dynamics simulations and MM-GBSA binding free-energy calculations. Three selected compounds were further evaluated in vitro, among which Rubimaillin showed notable anticancer activity with IC₅₀ values of 1.10 ± 0.12 µM and 2.07 ± 0.02 µM against MIA PaCa-2 and PANC-1 cell lines, respectively, while displaying low toxicity toward non-tumorous HEK-293 cells (CC₅₀ = 38.92 ± 8.49 µM). Rubimaillin also significantly inhibited cell migration and modulated key oncogenic biomarkers, including reduced KRAS protein levels, downregulation of BCL2, SOX9, and LC3 gene expression, and upregulation of p53 expression. Overall, these findings suggest that Rubimaillin may represent a suitable candidate for further investigation as a KRAS^G12D-targeted anticancer agent and demonstrate the value of integrating computational screening with natural product-based drug discovery approaches.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7993-8015"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759325","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":"Pyrimidine derivatives as anticancer agents targeting kinases: design strategies, biological evaluation, and structure-activity relationship insights.","authors":"Manjushree Bv, Gurubasavaraja Swamy Purawarga Matada, Rohit Pal, Abhishek Ghara, Anguraj Moulishankar","doi":"10.1007/s11030-026-11603-5","DOIUrl":"10.1007/s11030-026-11603-5","url":null,"abstract":"<p><p>Protein kinases such as EGFR, VEGFR, PI3K, and CDKs play crucial roles in tumor progression and therapeutic resistance, making them prime targets in anticancer drug development. Among the structural scaffolds explored for designing selective kinase inhibitors, pyrimidine and its derivatives have emerged as highly privileged heterocycles due to their unique electronic properties, hydrogen-bonding capacity, and structural compatibility with kinase ATP-binding pockets. This review summarizes, recent advances in the design, synthesis, structure-activity relationship, and biological evaluation of pyrimidine-based inhibitors highlighting structural modification strategies such as molecular hybridization, bioisosterism, isosteric replacement and scaffold hopping approaches. The findings discussed in this review demonstrates that rational structural modification of the pyrimidine scaffold enables potent, selective, and multitarget kinase inhibition, positioning the versatility of pyrimidine derivatives as a privileged framework for the development of next-generation kinase-targeted anticancer agents with the potential to overcome therapeutic resistance.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7811-7859"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275559","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":"Recent advancements in microtubule targeting agents for breast cancer: design strategies and pharmacological insights.","authors":"Paramjeet Kaur, Rajiv Sharma","doi":"10.1007/s11030-026-11594-3","DOIUrl":"10.1007/s11030-026-11594-3","url":null,"abstract":"<p><p>Despite advances in the current treatment strategies for breast cancer management, chemotherapeutic resistance and recurrence are now recognised as a substantial global health problem. Microtubule-targeting agents are key clinical candidates in breast cancer therapy that abrogate tubulin dynamics, lead to arrest in mitosis, and enhance apoptosis of cancer cells. However, traditional agents like taxanes and vinca alkaloids suffer from the serious issue of toxicity, suboptimal pharmacokinetics, and multidrug resistance. Novel scaffolds and molecular hybrids have been reported to exhibit potent activity against resistant breast cancer cells by targeting the colchicine or taxane sites of tubulin. In addition, multi-targeting and dual-targeting ligands showed interesting combinatory effects. This review discusses the design strategies, structure-activity relationship studies, and pharmacological knowledge of a new class of microtubule-targeting agents to encourage further scope in the development of next-generation, selective, and safer antimitotic agents for better management of breast cancers.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7715-7733"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979753","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":"Deep learning architectures achieve state-of-the-art (SOTA) accuracy in protein secondary structure prediction.","authors":"Zahra Nikfarjam, Majid Jafari, Farshid Zargari","doi":"10.1007/s11030-026-11570-x","DOIUrl":"10.1007/s11030-026-11570-x","url":null,"abstract":"<p><p>Protein secondary structure prediction represents an important intermediate step between a protein's linear amino acid sequence and its three-dimensional structure, with broad implications for synthetic biology, drug development, and disease research. Although experimental techniques such as X-ray crystallography provide highly accurate structural information, they are labor-intensive, time-consuming, and costly, which has motivated the development of computational alternatives. Early machine-learning approaches to this problem were limited in their ability to capture complex sequence-structure relationships. The introduction of convolutional and recurrent neural networks improved hierarchical feature extraction, and predictive performance advanced further with transformer-based architectures such as AlphaFold2. This review outlines recent advances in hybrid model design, benchmark datasets, and evaluation metrics for protein secondary structure prediction. We also discuss current methodological limitations, including data dependency and dataset bias, and outline future directions such as cross-species validation, uncertainty-aware modeling, and the still-emerging potential of incorporating heterogeneous biological data into next-generation PSSP frameworks.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7623-7643"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809409","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":"Discovery, synthesis, and anti-cancer activity of N-CF₃-benzimidazoles.","authors":"Qigang Sun, Jia-Yi Li, Qingjiang Li, Yu Zhang","doi":"10.1007/s11030-026-11616-0","DOIUrl":"10.1007/s11030-026-11616-0","url":null,"abstract":"<p><p>Benzimidazole is a privileged heterocyclic pharmacophore widely used in medicinal chemistry, while the N-trifluoromethyl (N-CF₃) moiety represents a valuable modification strategy to optimize the druggability of small molecules. However, systematic studies on the antitumor activity of N-CF₃-benzimidazoles remain scarce to date. In this study, the N-CF₃-substituted benzimidazole scaffold was identified as a core active antitumor motif through phenotypic screening of our in-house compound library. Leveraging our established synthetic methodology, a library of 39 structurally diverse N-CF₃-benzimidazole derivatives was prepared and systematically evaluated for their in vitro antiproliferative activity against three human cancer cell lines (786-O, A498, HepG2) using the CCK-8 assay. The results showed that most compounds exhibited varying degrees of antiproliferative activity at 10 µM. Notably, the hit compound 15 displayed micromolar GI₅₀ values and showed the most potent activity against 786-O cells. Furthermore, in silico target prediction of representative derivatives suggested potential interactions with a panel of kinases and epigenetic modulators, providing preliminary insights into their antitumor mechanism. This work characterizes the antitumor potential of N-CF₃-benzimidazoles, offering a critical underpinning for the development of novel antitumor drug candidates.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7459-7465"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154851","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":"AI-driven discovery of natural product-derived FAK1 inhibitors for idiopathic pulmonary fibrosis.","authors":"Xing-Yi Chen, Mei-Hong Lu, Bin Li, Ya Zhou, Li Liu, Hao Yang, Qiu-Yu Wang, Lin Chang, Yu-Lan Zhao, Dong-Mei Wang, Bin Li, Ben-Rong Mu","doi":"10.1007/s11030-026-11556-9","DOIUrl":"10.1007/s11030-026-11556-9","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8017-8044"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759262","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}