Molecular Diversity最新文献

{"title":"Novel 1,2,4-oxadiazole derivatives containing a sulfone moiety: Design, synthesis, biological activity, and antivirulence factors.","authors":"Zongnan Zhu, Xing Liu, Yue Zou, Dengyue Liu, Wenlei Chen, Jixiang Chen","doi":"10.1007/s11030-025-11338-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11338-9","url":null,"abstract":"<p><p>To discover novel antibacterial agents, a series of 28 1,2,4-oxadiazole derivatives containing sulfone moiety were designed, synthesized, and evaluated for their antibacterial activity. Some of the target compounds exhibited promising antibacterial properties. Among them, compound G26 showed excellent activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC₅₀ value of 24.3 mg/L, which was superior to the positive control agents bismerthiazol (EC₅₀ = 54.1 mg/L) and thiodiazole copper (EC₅₀ = 92.3 mg/L). Compound G26 exhibited a protective efficacy of 30.9% against rice bacterial leaf blight, which was comparable to that of thiodiazole copper (31.2%) but lower than that of bismerthiazol (48.7%). Mechanistically, G26 inhibited the growth and proliferation of Xoo by suppressing virulence factors (including extracellular polysaccharides, cell membrane integrity, motility, xanthomonadin, and extracellular amylase), increasing membrane permeability, and altering the bacterial surface morphology, ultimately leading to bacterial death. In addition, some of the compounds demonstrated good antifungal activity. Specifically, compounds G6, G9, G12, and G17 exhibited EC₅₀ values of 25.7, 17.7, 29.5, and 24.3 mg/L, respectively, against Botrytis cinerea, outperforming the commercial fungicide fluopyram (EC₅₀ = 106.7 mg/L). Compound G26 may serve as a lead compound for the development of new antibacterial agents through further structural optimization.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342505","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":"Virtual screening and experimental validation of small-molecule compounds targeting AR in prostate cancer.","authors":"Zhongqiang Fan, Xuexue Hao, Weiren Chen, Zhunan Xu, Qihua Wang, Muwei Li, Hao Zhang, Congzhe Ren, Yutong Chen, Jianping Lin, Xiaoqiang Liu","doi":"10.1007/s11030-025-11359-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11359-4","url":null,"abstract":"<p><p>Prostate cancer ranks as the second most prevalent malignancy among men, with its progression predominantly driven by androgen receptor (AR) signaling. Despite the centrality of androgen deprivation therapy (ADT) in managing advanced prostate cancer, the emergence of resistance culminating in castration-resistant prostate cancer (CRPC) remains a formidable challenge. In this study, an integrative strategy for virtual screening was developed using a machine learning-based model implemented with Random Forest, followed by molecular docking. This strategy was employed to screen approximately 1,500,000 compounds, ultimately narrowing them down to 20 candidates. Among these, 8020-1599 and C301-6562 were identified as effective AR inhibitors. In vitro assays demonstrated that these compounds significantly inhibited the proliferation, migration, and invasion of prostate cancer cells, exhibiting efficacy comparable to that of the clinical standard, enzalutamide. In vivo experiments further validated their antitumor activity, demonstrating significant tumor growth inhibition without causing notable toxicity. Mechanistically, 8020-1599 and C301-6562 disrupted AR nuclear translocation and its downstream signaling pathways, leading to a marked reduction in the expression of AR-regulated genes FKBP5 and KLK3. This study highlights a promising approach for developing highly effective and minimally toxic AR inhibitors, although further research is required to assess their long-term safety and potential effects on alternative signaling pathways.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297824","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 advances in Pyrazolo[3,4-d]pyrimidine-based dual inhibitors in the treatment of cancers.","authors":"Hanrui Jiang, Nan Li, Ruosong Qin, Siyu Lin, Xuelian Wang, Chunyan Li, Jiwei Shen, Ye Chen, Ju Liu, Shi Ding","doi":"10.1007/s11030-025-11379-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11379-0","url":null,"abstract":"<p><p>Cancer remains a paramount threat to global health and constitutes a critical frontier in contemporary drug discovery. The pyrazolo[3,4-d]pyrimidine scaffold represents a unique chemical architecture that merges purine and pyrimidine pharmacophores, enabling profound exploration and clinical translation across anti-cancer therapeutic domains. The development of dual-target inhibitors represented a compelling strategy. This combinatorial approach not only amplified pharmacological efficacy through synergistic pathway suppression but also reduced the likelihood of resistance development by disrupting redundant survival networks. This review focused on the emerging paradigm of pyrazolo[3,4-d]pyrimidine-based dual-target inhibitors in oncology. Specifically, we systematically analyzed seven distinct dual-inhibition paradigms: AK/CDK1, HDAC/Topo II, CDK2/GSK-3β, Src/Bcr-Abl, BRAF V600E/VEGFR2, EGFR/PDE5, and EGFR T790M/HER2. Comprehensive insights were provided into the rational design principles, the structure-activity relationships (SARs), and molecular mechanisms underlying these innovative therapeutics. Furthermore, we proposed forward-looking strategies for design, ADME profiling, and toxicity mitigation to guide the translational development of pyrazolo[3,4-d]pyrimidine derivatives in cancer therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145297857","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":"Bayesian active learning-aided structure-based virtual screening reveals novel inhibitors of mutant IDH1.","authors":"Sen Xu, Yue Yang, Chao Chen, Xiaolong Lv, Xiaojun Lei, Haigang Wu, Yuguang Lei","doi":"10.1007/s11030-025-11381-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11381-6","url":null,"abstract":"<p><p>Mutations in Isocitrate dehydrogenase 1 (IDH1) create neoenzymatic activity that drives the oncometabolite 2-hydroxyglutarate, motivating selective small-molecule inhibitors. Here, we present a dual-strategy pipeline that integrates Bayesian neural network (BNN)-aided structure-based virtual screening (SBVS) with an active-learning-guided generative design loop. Beginning from ~ 3.1 million candidate structures, a BNN provides calibrated activity means and uncertainties that drive upper-confidence-bound acquisition, while a Transformer-based generative model proposes scaffold-diverse analogs optimized for predicted binding affinity, physicochemical constraints, and ADMET priors. Shortlisted compounds undergo consensus docking and triplicate 200-ns molecular dynamics (MD) per complex, followed by free energy decomposition and in silico ADMET profiling. We identify five chemically diverse leads (XS-1-XS-5) with stable binding modes and favorable predicted developability relative to AG-120. Residue-level analyses reveal context-dependent contributions-most notably His132, which exhibits high conditional ΔΔG despite lower contact frequency-supporting targeted SAR hypotheses. Our results demonstrate that coupling uncertainty-aware prioritization with goal-directed generation accelerates the discovery of selective mutant-IDH1 inhibitors while preserving chemical diversity and downstream viability.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290571","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":"Prediction of drug-induced nephrotoxicity based on deep learning algorithm and molecular fingerprints.","authors":"Shuailong Wang, Yan Li","doi":"10.1007/s11030-025-11376-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11376-3","url":null,"abstract":"<p><p>Drug-induced nephrotoxicity (DIN) is an infrequent adverse reaction to medications and represents a complex clinical outcome influenced by multiple factors. Predicting DIN using preclinical animal models remains challenging, and in silico approaches have emerged as promising alternatives for DIN risk assessment. A high-quality dataset consisting of 1,018 compounds was constructed in this study. Compounds in this dataset were systematically collected from five authoritative sources: the SIDER, FDA, ChEMBL, DrugBank, and literature on \"drug-induced nephrotoxicity\" published in the past decade (screened via keyword search on PubMed). Clear criteria were followed for compound screening and label annotation: using \"kidney,\" \"nephrotoxicity,\" \"kidney injury,\" and \"kidney disease\" as core search terms, compounds retrieved that were clearly associated with kidney injury or could induce kidney disease were classified into the positive set (DIN = 1); compounds with no records of renal adverse reactions, or those explicitly having renal protective effects or used for treating renal diseases, were classified into the negative set (DIN = 0). Ultimately, a dataset of 1018 compounds with clear labels and reliable sources was integrated. The 42 classification models, which depended on six different molecular fingerprints, were built via deep neural network (DNN) and six machine learning algorithms. A comparative study demonstrated that models utilizing DNN consistently surpassed traditional machine learning approaches across six molecular fingerprint types. Notably, the ECFP_6 fingerprint exhibited the highest performance, achieving an area under the receiver operating characteristic curve (AUC) of 75.9%, an accuracy (ACC) of 71.4%, and an F1-score of 76.0%. Furthermore, the SHapley Additive exPlanations (SHAP) algorithm was applied to interpret the predictions of the high-performing models, identifying key structural fragments associated with DIN. The ten most influential substructures, identified based on their impact on model predictions, were chosen as early warning markers for future DIN screening research. Overall, these results suggest that DNN models utilizing molecular fingerprints can function as dependable and efficient tools for assessing nephrotoxicity risk in potential drug candidates during the initial phases of drug development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278684","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":"Quercetin as a selective quorum sensing inhibitor: in silico and in vitro analyses against Pseudomonas syringae with limited impact on plant growth-promoting bacteria.","authors":"Shivangi Bhatt, Jignesh Prajapati, Dweipayan Goswami, Meenu Saraf","doi":"10.1007/s11030-025-11363-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11363-8","url":null,"abstract":"<p><p>Quorum sensing (QS) is a bacterial communication mechanism that coordinates gene expression and regulates population-dependent behaviors such as biofilm formation, virulence, and antibiotic resistance. Pseudomonas syringae, a major plant pathogen, causes bacterial blight in legumes, significantly reducing crop productivity. In contrast, plant growth-promoting bacteria (PGPR) produce secondary metabolites that enhance plant growth and protect against pathogens. This study aimed to identify plant-derived compounds capable of selectively disrupting the QS of P. syringae without adversely affecting beneficial PGPR strains, using a combined in silico and in vitro approach. The QS-specific mode of action was functionally confirmed using a Chromobacterium violaceum biosensor assay, which revealed potent, dose-dependent inhibition of violacein pigment. Molecular docking and MM-GBSA (Molecular Mechanics Generalized Born Surface Area) analyses identified quercetin as the most potent compound, exhibiting strong binding affinity (docking score: - 10.363 kcal/mol; binding energy: - 55.89 kcal/mol) to QS-related proteins in P. syringae. Beneficial bacteria, including Klebsiella pneumoniae and Sinorhizobium meliloti, showed lower affinities to quercetin. Chromobacterium violaceum, a well-known QS reporter strain used as a control, exhibited the lowest sub-minimum inhibitory concentration (47.22 μg/mL). Experimentally, quercetin inhibited bacterial growth by 90-95% at 1024 μg/mL. The sub-MIC values for P. syringae, K. pneumoniae, and S. meliloti were 156.7, 242.6, and 535.7 μg/mL, respectively. At 64 μg/mL, quercetin suppressed biofilm formation by 92% in P. syringae, 95-98% in K. pneumoniae and S. meliloti, and 78% in C. violaceum. These findings highlight quercetin's selective disruption of QS and biofilm formation in P. syringae, underscoring its potential as a targeted biocontrol agent for legume crop protection.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273334","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 discovery and validation of 4'-O-methylochnaflavone as a novel HSP90AB1 inhibitor for hepatocellular carcinoma treatment.","authors":"Yuan Yang, Xufeng Ning, Ming Chen, Kangle Gao, Tao Guo, Lingshan Zhou, Bin Zeng, Weiwei Zhou","doi":"10.1007/s11030-025-11370-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11370-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a global health issue with limited therapeutic efficacy. Heat shock proteins (HSPs) could enhance adaptation to the oxygen-deprived tumor microenvironment (TME), leading to chemotherapy resistance. Regulating HSP to improve the immune microenvironment may enhance tumor treatment efficacy. However, pharmacological agents targeting HSPs to reverse the immunosuppressive TME remain scarce. In this study, we integrated bioinformatic analysis, virtual screening, molecular docking, molecular dynamics (MD) simulations, and experimental validation to identify therapeutic targets and potential natural product-derived inhibitors. Differentially expressed hypoxia-related immune genes (HRIGs) associated with HCC prognosis were first identified using bioinformatic analysis. Venn diagram revealed HSP90AB1 as the candidate target protein. Virtual screening of the TargetMol and MedChemExpress (MCE) compound libraries was performed, and preliminary molecular docking identified 4'-O-methylochnaflavone as the lead compound. The interaction between 4'-O-methylochnaflavone and HSP90AB1 was further evaluated by MD simulations and experimental validation. Surface plasmon resonance (SPR) assay demonstrated that 4'-O-methylochnaflavone could stably bind HSP90AB1. In vitro CCK-8 assays demonstrated that 4'-O-methylochnaflavone inhibited Hep3B cell proliferation in a time- and dose-dependent manner. Finally, Western blot analysis confirmed hypoxia-induced upregulation of HSP90AB1, which was significantly suppressed by 4'-O-methylochnaflavone. In conclusion, our study identifies 4'-O-methylochnaflavone is a promising HSP90AB1-targeting therapeutic candidate for HCC treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273363","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 of GPX3 as a key biomarker of placental ferroptosis in gestational diabetes mellitus via bioinformatics and clinical analysis.","authors":"Padmanaban M Abirami, K L Milan, M Anuradha, Kunka Mohanram Ramkumar","doi":"10.1007/s11030-025-11373-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11373-6","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) is characterized by glucose intolerance during pregnancy, and emerging evidence implicates dysregulated iron metabolism as a critical modulator of its pathogenesis. Ferroptosis, an iron-mediated cell death, has recently been studied in GDM, with research beginning to unravel the connection between iron-induced oxidative stress and placental dysfunction. In this study, we employed datasets from the Gene Expression Omnibus database to identify markers of ferroptosis that are associated with GDM. A total of 57 differentially expressed genes related to ferroptosis were identified. Feature selection was performed using machine learning approaches, including Boruta, Random Forest, and LASSO regression, to pinpoint the most critical genes. Among them, GPX3 emerged as the central biomarker linked to ferroptosis in GDM. We further validated GPX3 expression across various placental cell types using single cell RNA sequencing data. Further CIBERSORT analysis determined a significant association between GPX3 and several immune cell populations, including macrophages, B cells, monocytes, and T cells. Finally, mRNA expression of GPX3 was experimentally validated in placental samples from GDM patients, where it was found to correlate with a reduced sTFR/ferritin ratio, suggesting disrupted iron homeostasis. In conclusion, GPX3 is identified as a crucial immuno-ferroptotic biomarker in GDM, with potential diagnostic value. Integrating bioinformatics, machine learning, and clinical validation, this study highlights the role of GPX3 at the intersection of immune infiltration and iron metabolism, offering new insights for future diagnostic and therapeutic strategies in GDM.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273317","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":"Novel carbazole-triazole-thioether conjugates as multifunctional antimicrobial agents against phytopathogen.","authors":"Awei Zhang, Huiyan Quan, Danqing Wang, Guangqin Yang, Haizhen Zhang, Ling Tao, Lan Yang, Xiangchun Shen","doi":"10.1007/s11030-025-11377-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11377-2","url":null,"abstract":"<p><p>Carbazole and triazole derivatives exhibit diverse biological activities and pharmacological properties. Herein, we report a series of novel 1,2,4-triazole thioethers containing carbazole moiety and evaluate their biological activities. The results showed that some of the title compounds exhibited excellent antibacterial activities in vitro against Xanthomonas axonopodis pv. citri (Xac) in vitro. In particular, compound E36 exhibits the most excellent antibacterial effect against Xac, with an EC₅₀ value of 9.4 mg/L. This efficacy was significantly superior to those of the control drugs bismerthiazol (BMT, EC₅₀ values of 70.5 mg/L) and thiodiazole-copper (TDC, EC₅₀ values of 96.0 mg/L). Meanwhile, E36 also demonstrated a significant in vivo effect against Xac, with the therapeutic and protective efficacy of 48.57% and 51.96%, respectively, at a concentration of 200 mg/L, which was superior to TDC and equivalent to BMT. Additionally, E36 exhibited notable antifungal activity against Verticillium dahliae. Further mechanistic studies revealed that compound E36 attenuates the pathogenicity of Xac by suppressing bacterial motility and reducing extracellular polysaccharide (EPS) production. Concurrently, it enhances host disease resistance by upregulating the expression of the citrus rbcL protein, thereby promoting carbon fixation and improving photosynthetic efficiency. This work indicates that 1,2,4-triazole thioethers containing carbazole moiety has the potential to be developed as novel bactericidal agents.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231029","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 and development of N-Heterocyclic protease inhibitors for flaviviral infections: a synthetic and SAR-based review.","authors":"Rajarshi Nath, Md Jawaid Akhtar, Sudin Sundar Pradhan, Subarna Kanti Mal, Shambo Panda, Sumel Ashique, Arindam Maity, Krishnalekha Bandyopadhyay, Samiran Paul, Shah Alam Khan, Bhupender Nehra, Biplab Debnath, Fatimah M Al-Salem, Sabina Yasmin, Mohammad Yousuf Ansari","doi":"10.1007/s11030-025-11374-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11374-5","url":null,"abstract":"<p><p>Dengue, Zika, and West Nile viruses are major global health threats that belong to the genus Flavivirus and demand urgent attention. The viral proteases, particularly the viral protease complex (NS2B-NS3; NS2B: A small cofactor protein that activates NS3, NS3: A large multifunctional protein) complex, play a vital role in viral replication, making them prime targets for antiviral drug development. This review article has included the synthetic approach and Structure Activities Relationship (SAR) of such compounds, emphasizing how structural modifications in N-heterocyclic analogs affect inhibitory effectiveness toward proteases. Synthetic approaches such as click chemistry, cyclization, and bioisosteric replacements have been reviewed in order to enhance the selectivity and bioavailability of such molecules. Furthermore, computational modeling and molecular docking studies have been emphasized that support the rational drug design of reported molecules by predicting key binding interactions and optimizing pharmacokinetic parameters. In summary, this article underscores the importance of N-heterocyclic structures to develop viral protease inhibitors and provides direction for future antiviral drug development efforts. This review also highlights the potential of N-containing heterocycles as promising scaffolds for protease inhibition with an emphasis on their synthetic accessibility and capacity to engage in strong interactions within viral active sites. The present review also focuses on a future for the synthesis of nitrogenous heterocyclic analogs with a greater leadership of in silico approaches, including computational docking, fragment-based screening, and high-throughput synthesis techniques. Recent advances demonstrate that structural optimization of these heterocycles has led to compounds with encouraging antiviral activity, i.e., supported by computational insights. Looking forward, integrating in silico approaches with innovative synthetic methodologies is expected to accelerate development of selective and potent flaviviral protease inhibitors. Together, these efforts may pave the way for effective treatments against emerging flavivirus infections.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231023","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}