Molecular Diversity最新文献

{"title":"Identification of novel small molecules as potential SGLT2 inhibitors through combined virtual screening and experimental validation.","authors":"Fei Qin, Huicong Zeng, Li Zhou, Zhenhua Zhou, Yongxin Mao, Youyan Zeng, Rongxiang Guo, Kaixian Chen, Dongyu Zhao, Weiwei Yao, Bin Zhang, Qian Zhou, Bo Li","doi":"10.1007/s11030-025-11367-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11367-4","url":null,"abstract":"<p><p>The sodium-glucose co-transporter 2 (SGLT2) plays an important role in mediating glucose reabsorption within the renal filtrate and regulating blood glucose levels, which makes it a well-known target for diabetes mellitus. A number of SGLT2 inhibitors (SGLT2i) have been established as important antidiabetic drugs, and research on new SGLT2i with high affinity is ongoing. Herein, 101 compounds were screened from a compound library (approximately 16,000 compounds) using a virtual screening workflow that integrated various docking programs, pharmacophore modeling, and druggability filter. To verify the results of virtual screening, we established a HK-2 cell model with d-glucose derivative 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) for measuring glucose uptake via SGLT2. 12 candidate compounds were selected and purchased for subsequent experimental validation. Among these, 3 non-glycoside compounds significantly inhibited the 2-NBDG uptake in a dose-dependent manner and their IC₅₀ values for SGLT2 were 71.43 μM, 72.66 μM, and 91.44 μM, respectively. Mechanism studies demonstrated that all 3 compounds significantly downregulated SGLT2 level and activated silent information regulator 1 (SIRT1) expression in high-glucose-induced cell injury models. These findings confirmed the ability of these compounds to bind to SGLT2 and also revealed their potential mechanisms in regulating oxidative stress and metabolism. Furthermore, molecular dynamics simulation indicated the high binding stability of SGLT2 and 3 compounds complexes during a 100-ns simulation period. In conclusion, our results identified 3 potential SGLT2i and preliminarily elucidated their mechanism of action, which lays the foundation for the development of novel and potent non-glycoside SGLT2i in future.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184481","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":"Unveiling the anticancer potential of medicinal plants: metabolomics and analytical tools in phytomedicine.","authors":"Nisha Bansal, Ali M Alaseem, Arockia M Babu, Glowi Alasiri, Thakur Gurjeet Singh, Yogita Tyagi, Geetika Sharma","doi":"10.1007/s11030-025-11362-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11362-9","url":null,"abstract":"<p><p>Metabolomics accounts for the metabolic alterations and identification of novel biomarkers in the war to combat cancer. This review explores advancements in metabolomics, emphasizing its application in understanding cancer-associated metabolic pathways and phytochemical interactions. Herein, we have explored the literature overview on the spectrometric integration of nuclear magnetic resonance with mass spectrometric methods for comprehensive metabolite profiling, enabling the identification and the documentation of critical biomarkers, allowing the early cancer detection, and monitoring its prognosis. We also look at metabolic dysregulations in cancer, such as oncometabolites and the Warburg effect, which aid in the growth of tumors. Natural products have been thoroughly examined for their anticancer potential, and metabolomics provides a systematic approach to evaluating their efficacy. This review highlights various plant-based bioactive compounds, including curcumin, genistein, and withaferin A, which have demonstrated anticancer properties through metabolomic profiling. Furthermore, we discuss next-generation metabolomics and pharmaco-metabolomics for precision oncology and personalized cancer treatment. By integrating metabolomics with emerging bioinformatics tools, this review provides a comprehensive framework for biomarker discovery, early cancer detection, and therapeutic advancements. The insights presented herein underscore the potential of metabolomics in bridging traditional cancer research with innovative prevention strategies, ultimately contributing to the advancement of more precise and effective targeted cancer therapies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181731","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":"Targeting viral RNA pseudoknots: a multi-level computational approach to identify RNA-binding novel small molecules.","authors":"Neha Jeena, Sahal Bin Saleem Cp, Shubham Srivastava, Devesh M Sawant, Inshad Ali Khan","doi":"10.1007/s11030-025-11366-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11366-5","url":null,"abstract":"<p><p>The RNA pseudoknot of SARS-CoV-2 plays a pivotal role in - 1 programmed ribosomal frameshifting (- 1 PRF), which is essential for viral protein synthesis and replication. Targeting this RNA structural element offers a novel therapeutic strategy against COVID-19. In this study, we applied an integrative computational approach combining molecular docking, MM-GBSA binding free energy calculations, ADME-Tox profiling, and extended 500 ns molecular dynamics simulations to identify small molecules capable of disrupting the pseudoknot function. F2879-5340 emerged as a promising RNA-targeting candidate, demonstrating stable interactions with key pseudoknot nucleotides and favorable ΔG_bind values. Compared to the control compound Nafamostat, F2879-5340 exhibited superior predicted pharmacokinetic properties, including higher intestinal absorption, better bioavailability, and no mutagenic potential. These results suggest that F2879-5340 is a potent candidate for further experimental validation as an orally bioavailable - 1 PRF inhibitor. This work presents a novel computational pipeline for RNA-targeted drug discovery in the context of SARS-CoV-2.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147422","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":"Integrative genomics and structural bioinformatics uncovers AMR-associated drug targets and pqsH inhibitors in multidrug-resistant Pseudomonas aeruginosa JJPA01.","authors":"Bhuvaneswari Narthanareeswaran, Nagarajan Hemavathy, Sampathkumar Ranganathan, Shaslinah Nathar, Chitra Jeyaraj Pandian, Jeyaraman Jeyakanthan","doi":"10.1007/s11030-025-11365-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11365-6","url":null,"abstract":"<p><p>The rise of multidrug-resistant (MDR) Pseudomonas aeruginosa poses a significant threat in clinical settings due to its intricate antimicrobial resistance mechanism, biofilm formation, quorum sensing, and efflux pump-mediated antibiotic tolerance capability. The progressive decline in the efficacy of conventional antibiotics necessitates the development of new treatment strategies. Disrupting the Quorum sensing, a pivotal regulator of virulence and biofilm-associated resistance presents a promising anti-virulence strategy. An integrated Subtractive genomics and in silico drug discovery approach was applied to the complete proteome of P. aeruginosa JJPA01, excluding paralogous, human homologous, and non-essential proteins to identify virulence-associated targets. 27 pathogen-specific pathway proteins were identified, with pqsH (WP_003090354.1), a key monooxygenase in the PQS quorum-sensing system. Potential inhibitors for pqsH were identified using High-Throughput Virtual Screening (HTVS) on natural compounds from the COCONUT, CMNPD, MNPD, Seaweed, and Specs databases. The docking study identified five compounds with the best binding affinities, ranging from - 6.6 to - 7.7 kcal/mol. However, only CNP0000215 and CNP0007440 exhibited higher binding affinity to the pqsH protein than the cofactor Flavine Adenine Dinucleotide. With its established role in Antimicrobial Resistance and Virulence, pqsH has been selected as a therapeutic target and CNP0000215 as a promising PQS inhibitor to disrupt biofilm formation and combat antimicrobial resistance. These findings lay the groundwork for the strategic design of novel anti-therapeutics offering a promising strategy to inhibit persistent infections and resistance mechanisms in P. aeruginosa.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136107","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":"A decade of progress in transition metal-catalyzed sulfoxide reductions.","authors":"Mohammad Abu Shuheil, Radwan Ali, Munthar Kadhim Abosaoda, M M Rekha, Mosstafa Kazemi, Subhashree Ray, Kattela Chennakesavulu, Renu Sharma","doi":"10.1007/s11030-025-11346-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11346-9","url":null,"abstract":"<p><p>The deoxygenation of sulfoxides to sulfides is a fundamental reaction in organic synthesis, widely used in pharmaceuticals, materials science, and natural product chemistry. Traditional methods require stoichiometric reagents under harsh conditions, but transition metal catalysis now allows milder, more selective, and environmentally friendly deoxygenation. This review highlights recent advances in catalytic systems based on Mo, Ir, Mn, Co, and other metals, focusing on their mechanisms, substrate scopes, and sustainable design. Innovations in recyclable catalysts, green solvents, earth-abundant metals are also discussed, emphasizing how modern approaches enhance both efficiency and environmental compatibility.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147343","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 of potential RSV fusion protein inhibitors from benzimidazole derivatives using QSAR, molecular docking, and ADMET evaluation methods.","authors":"Yini Xie, Runqing Jia, Tengjiao Fan, Shuo Chen, Ting Ren, Na Zhang, Lijiao Zhao, Rugang Zhong, Guohui Sun","doi":"10.1007/s11030-025-11360-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11360-x","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants, the elderly, and immunocompromised individuals worldwide. The pathogenic mechanism of RSV is closely linked to the membrane fusion process mediated by its fusion glycoprotein (F protein), which has consequently emerged as a critical target for developing anti-RSV therapeutics. At present, there is a lack of specific clinical treatments for RSV, and traditional drug discovery approaches are often time-consuming and expensive. In this context, quantitative structure-activity relationship (QSAR)-assisted drug design offers notable advantages. In this study, we collected a dataset consisting of 156 benzimidazole derivatives against F protein from publicly available sources. Transferable, reproducible, and interpretable 2D-QSAR inhibitory activity and cytotoxicity prediction models were constructed using Genetic Algorithm (GA) and Multiple Linear Regression (MLR). Following rigorous statistical validation, the best inhibitory activity model achieved R² = 0.8740, <math><msubsup><mi>Q</mi> <mrow><mtext>Loo</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.8272, <math><msubsup><mi>R</mi> <mrow><mtext>test</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.8273, <math><msubsup><mi>Q</mi> <mrow><mtext>Fn</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.8033-0.8492, CCC_test = 0.8782, MAE_test = 0.3014; the best cytotoxicity model was of R² = 0.7573, <math><msubsup><mi>Q</mi> <mrow><mtext>Loo</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.6926, <math><msubsup><mi>R</mi> <mrow><mtext>test</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.7707, <math><msubsup><mi>Q</mi> <mrow><mtext>Fn</mtext></mrow> <mn>2</mn></msubsup> </math> = 0.7298-0.8656, CCC_test = 0.8639, MAE_test = 0.1342. The optimal inhibitory activity model was used to perform virtual screening on 912 benzimidazole derivatives retrieved from the PubChem, and identified 234 derivatives with better inhibitory activity than the reference JNJ-53718678. Among these, 152 derivatives were found to possess better docking binding energies than JNJ-53718678. Furthermore, we used the optimal toxicity model to assess their cytotoxicity, and identified 23 derivatives with predicted cytotoxicity lower than that of JNJ-53718678. Finally, through drug-likeness evaluation, ADMET analysis and molecular dynamics simulation, we obtained eight potential RSV inhibitors with higher inhibitory activity, lower cytotoxicity, and better pharmacokinetic properties compared to JNJ-53718678.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136157","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":"Progress and application of activity-based protein profiling for the discovery of natural product targets.","authors":"Jinfang Qin, Shun Zhang, Yongyi Pan, Xiaocan Lei, Zhenwei Guo, Qin Xie, Kongwei Huang, Peng Huo","doi":"10.1007/s11030-025-11361-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11361-w","url":null,"abstract":"<p><p>Identifying natural products (NPs) targets is of great significance for the study of drug function mechanisms and the discovery of new compounds acting on the targets. Chemical proteomics technologies provide new perspectives, among which activity-based Protein Profiling (ABPP) has attracted much attention as a research hotspot. In this paper, we systematically review the application of various chemical proteomics technologies in natural product target identification, in which the development of ABPP is elaborated in detail, including the traditional biotin-labeled probe technology, the application of bioorthogonal strategy and photoaffinity cross-linking reaction of ABPP (AfBPP) and their advantages and disadvantages. Meanwhile, We also illustrate the joint application of ABPP with other technologies to demonstrate the innovative value of technology integration. Finally, the application examples of ABPP were introduced by categorizing from two perspectives of natural product types and disease research directions, showing the important value and unique advantages of ABPP in NPs target research, such as precisely identifying targets and providing key information for new drug development. However, each chemical proteomics technology still faces various challenges, such as the optimization of ABPP probe design and the control of the effect on the physiological state of the cell, which need to be further improved and perfected in the future to accelerate the drug development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123834","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":"Targeting p53-MDM2 pathway with novel triazole-oxazole hybrids: a fragment-based drug discovery approach for next-generation cancer therapies.","authors":"Apurva Prajapati, Hitesh Patel","doi":"10.1007/s11030-025-11364-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11364-7","url":null,"abstract":"<p><p>The tumor suppressor protein p53 plays a pivotal role in regulating key cellular processes, including cell cycle arrest, apoptosis, and DNA repair. Its negative regulator, MDM2, binds to the N-terminal domain of p53 and promotes its degradation, leading to the function inactivation of p53 in many cancers. Disrupting the p53-MDM2 interaction is thus an attractive therapeutic strategy, especially in tumors retaining wild-type p53. In this study, we applied a comprehensive in silico approach combining Fragment-Based Drug Discovery (FBDD), molecular docking, R-group enumeration, MM-GBSA binding energy estimation, ADMET prediction, MD simulations, DFT analysis to identify the novel p53-MDM2 inhibitors. Key findings demonstrated that the designed triazole-oxazole hybrids exhibited stable binding with critical MDM2 residues, improved solubility-driven pharmacokinetic behavior, and favorable electronic properties compared with reference inhibitor. Importantly, solubility-guided fragment design not only improved hit quality but also provided scaffolds with strong therapeutic potential. Overall, this study highlights triazole-oxazole hybrids as promising candidates for p53 reactivation and establishes a rational basis for their further biological evaluation in anticancer therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123827","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":"New 1,2,3-triazole-linked (±)-agrimonolide derivatives as anti-ulcerative colitis agents inhibiting JAK1/STAT3 pathways.","authors":"Xiao Zhang, Ming-Qian Ju, Heng-Li Yang, Chun-Fei Zhang, Mao-Kui Huang, Yan-Ping Li, Chun-Ping Wan, Ze-Wei Mao","doi":"10.1007/s11030-025-11368-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11368-3","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease that is very difficult to cure. In this study, we have designed and synthesized a series of new 1,2,3-triazole-linked (±)-Agrimonolide derivatives and evaluated their anti-inflammatory activities. The in vitro results demonstrated that most triazole derivatives effectively inhibited NO production, and most compounds exhibited better anti-inflammatory activity than that of (±)-Agrimonolide and positive drug Dexamethasone. The further in vivo tests indicated that 6d could inhibit the release of inflammatory mediators in the colon tissue and alleviate Ulcerative colitis by inhibiting JAK1/STAT3 pathways.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129743","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":"TMolNet: a task-aware multimodal neural network for molecular property prediction.","authors":"Cao Han, Xianghong Tang, Jianguang Lu","doi":"10.1007/s11030-025-11350-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11350-z","url":null,"abstract":"<p><p>Molecular property prediction plays a vital role in drug discovery, materials science, and chemical biology. Although molecular data are intrinsically multimodal-comprising 1D sequences or fingerprints, 2D topological graphs, and 3D geometric conformations-conventional approaches often rely on single-modal inputs, thereby failing to leverage cross-modal complementarities and limiting predictive accuracy. To overcome this limitation, we propose TMolNet, a task-aware deep learning framework for adaptive multimodal fusion. The architecture integrates modality-specific feature extractors to learn distinct representations from 1D, 2D, and 3D inputs, reducing the bias caused by incomplete or under-represented modalities. A contrastive learning scheme aligns the representations across modalities within a shared latent space, enhancing semantic consistency. Furthermore, a novel task-aware gating module dynamically modulates the contribution of each modality based on both data characteristics and task requirements. To promote balanced modality usage during training, we introduce a modality entropy regularization loss, which encourages diversity and stability in learned representations. Comprehensive experimental results on multiple benchmark datasets show that TMolNet achieves competitive performance against existing advanced methods in predictive accuracy and generalization. These findings underscore the efficacy of our approach and advance the state-of-the-art in multimodal molecular property prediction.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102582","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}