Molecular Diversity最新文献

{"title":"Hyp-retro: hypernetwork-guided preference-conditioned retrosynthetic planner.","authors":"Jingwen Wang, Shuan Liu, Shaoye Zhang, Jianbo Qiao, Guanhe Li, Hanjun Zhao, Xiangxiang Zeng, Jinjin Li, Changhang Lin, Chen Su, Leyi Wei","doi":"10.1007/s11030-026-11694-0","DOIUrl":"10.1007/s11030-026-11694-0","url":null,"abstract":"<p><p>Retrosynthetic planning is a core task in computer-aided synthesis design. Existing multi-step retrosynthesis methods mainly focus on route accessibility and search success rates. However, in practical synthesis, route quality depends partly on yield, whose importance may vary across applications. Existing methods often struggle to adjust their search strategies according to changing yield preferences. To address this problem, we propose Hyp-Retro, a hypernetwork-guided and preference-conditioned retrosynthetic planning model. Hyp-Retro first collects candidate-pool decision data through a yield-guided search process. It then constructs a hypernetwork-driven tree policy network conditioned on yield preference, allowing the model to adjust candidate-node scores under different preference settings. On this basis, online reinforcement learning is employed to fine-tune the policy network, further enhancing the model's long-horizon decision-making capability and preference alignment in realistic search environments. Experimental results show that Hyp-Retro outperforms comparative methods in terms of search success rate and route yield. Moreover, it can adaptively adjust its planning strategy under different yield preferences, thereby generating high-quality retrosynthetic routes that better satisfy target-specific requirements.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10673-10684"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786760","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":"Machine learning-driven drug repurposing and computational validation for Nipah virus.","authors":"Shivangi Sharma, Pragya D Yadav, Sarah Cherian","doi":"10.1007/s11030-026-11708-x","DOIUrl":"10.1007/s11030-026-11708-x","url":null,"abstract":"<p><p>The recurring Nipah virus outbreaks and the lack of effective antiviral therapies, emphasize the urgent need for effective therapeutic interventions. Given the sporadic and unpredictable nature of NiV outbreaks, drug repurposing offers a time-efficient alternative to the development of novel antivirals. In this study, we leveraged machine learning (ML) techniques to accelerate the process of identifying potential therapeutic candidates. Several supervised ML models such as Support Vector Machines, Random Forest, Logistic Regression, Decision Tree, k-Nearest Neighbors, Artificial Neural Networks, and Ridge Classifier were implemented using publicly available NiV inhibitor datasets (viz. Anti-Nipah, NVIK, PubChem) as well as literature review (n = 211 compounds). Among these, the Random Forest model demonstrated highest predictive performance, achieving high accuracy on both training (95%) and testing (86%) datasets. The optimized model was subsequently applied to screen FDA-approved, preclinical, clinical, and antiviral drug libraries (comprising 9021 compounds) to identify potential anti-NiV candidates. The shortlisted compounds underwent further validation through molecular docking to evaluate binding affinity and molecular dynamics simulations to assess structural stability and interactions with key viral targets, including the glycoprotein and RNA-dependent RNA polymerase (RdRp). Based on docking scores and molecular dynamics stability, we identified three and five promising candidates: 2,3,4,5,6-Pentagalloylglucose, Echinacoside, Parishin A, and Neohesperidin dihydrochalcone, Naringin dihydrochalcone, Diosmin, Orientin, Amikacin, against the glycoprotein and RdRp respectively. This integrative approach, combining ML, drug repurposing, and computational validation, aims to expedite the discovery of effective therapeutic agents against the Nipah virus and strengthen preparedness for future outbreaks.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10787-10815"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849409","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 aloe-emodin as an antidepressant agent by targeting RANBP9.","authors":"Yangyang Yang, Dezhong Sun, Qingyun Jia, Bing Zhu, Huaiqing Lv, Fengyuan Che","doi":"10.1007/s11030-026-11688-y","DOIUrl":"10.1007/s11030-026-11688-y","url":null,"abstract":"<p><p>Excitotoxicity is a core pathological mechanism underlying various neurological disorders, including depression. It is primarily driven by the overactivation of NMDA receptors and disruption of calcium homeostasis. However, effective therapeutic interventions targeting this process remain limited. In this study, aloe-emodin was shown to reverse NMDA-induced reduction in cell viability, apoptosis, and calcium overload in a dose-dependent manner, while also attenuating NMDA-induced autophosphorylation of CaMKII. In a chronic unpredictable mild stress (CUMS) model, aloe-emodin significantly ameliorated depression-like behaviors, suppressed inflammatory responses and oxidative stress, and downregulated the expression of cleaved-PARP. By conducting biotin pull-down coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) analysis, and surface plasmon resonance (SPR) analysis, RANBP9 was identified as a direct molecular target of aloe-emodin, with a binding affinity (KD) of 716 nM. Molecular docking and molecular dynamics simulations revealed that aloe-emodin selectively binds to the His332 residue of RANBP9. Aloe-emodin promoted the degradation of RANBP9 via the ubiquitin-proteasome pathway by facilitating the interaction between RANBP9 and the E3 ligase CHIP. After RANBP9 was knocked down, the protective effects of aloe-emodin on cell viability and apoptosis were significantly weakened, confirming that the anti-excitotoxic activity of aloe-emodin is RANBP9-dependent. These findings collectively demonstrate that aloe-emodin is a novel and potent RANBP9-targeting compound with antidepressant activity and suggest that RANBP9 may serve as a promising target for developing antidepressant drugs.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10817-10836"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856886","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 dynamic profiling of dual acetylcholinesterase and monoacylglycerol lipase inhibitors for Alzheimer's disease.","authors":"The-Huan Tran, Thai-Son Tran, Thanh-Dao Tran","doi":"10.1007/s11030-026-11725-w","DOIUrl":"10.1007/s11030-026-11725-w","url":null,"abstract":"<p><p>Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction and neuroinflammation. Dual inhibition of acetylcholinesterase and monoacylglycerol lipase has emerged as a promising therapeutic approach. This study employed an integrative in silico workflow to identify potential dual acetylcholinesterase/monoacylglycerol lipase inhibitors from a molecular library derived from known inhibitors (rivastigmine, JZL-184, ABX-1431). A total of 365 compounds were screened via molecular docking, interaction-based filtering, ADME/toxicity prediction, and molecular dynamics simulations. Among them, compound H34 demonstrated a comparatively favorable overall computational profile, supported by MM/GBSA binding-energy estimates (ΔG_bind = - 30.96 and - 37.34 kcal/mol) and comparatively favorable structural stability metrics (RMSD, RMSF, Rg, and SASA) in the MD simulations. Further ProLIF interaction mapping and free energy landscape analysis supported the persistent interaction profile and conformational behavior of the H34-protein complexes. Additionally, H34 displayed favorable pharmacokinetic properties and low predicted acute toxicity. These results highlight H34 as a promising dual-target candidate for Alzheimer's disease therapy and illustrate the effectiveness of integrated computational strategies in early-stage drug discovery.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10945-10959"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885728","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 potent and selective MAO-B inhibitors from a morpholine-substituted chalcone library for neurodegenerative disorders.","authors":"Asmar Taghiyeva, Jaeyeop Lim, Abanish Biswas, Subodh Mondal, Ritika Uppal Mukherjee, Vinay N Basavanakatti, Nilüfer Bayrak, Venkatesan Jayaprakash, Man-Jeong Paik, Hoon Kim, Amaç Fatih TuYuN","doi":"10.1007/s11030-026-11733-w","DOIUrl":"10.1007/s11030-026-11733-w","url":null,"abstract":"<p><p>A series of targeted chalcones (TCs) was designed and synthesised using a microwave-assisted synthetic method to introduce diverse substituents at different positions on the phenyl ring. The structures of all nineteen TC analogues were confirmed by NMR, FTIR, and HRMS. In vitro tests against acetyl- and butyrylcholinesterases (AChE and BuChE), β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), and monoamine oxidases (MAO-A and MAO-B) showed that MAO-B was the most potent and selective. Among them, TC12 was the strongest inhibitor (IC₅₀ = 11.00 ± 1.0 nM; SI > 3636) and worked competitively (K_i = 7.16 ± 1.20 nM). In terms of IC₅₀ = 50.0 ± 1.0 nM and SI > 800, TC9 was ranked second. TC12 showed no time-dependent inhibition of MAO-B, and its MAO-B inhibition was reversible. Molecular docking studies revealed that TC12 establishes favourable interactions within the MAO-B active site, particularly through π-π stacking with aromatic cage residues (TYR398 and TYR435), while showing limited engagement with key regions of MAO-A. ADME predictions indicated that TC12 exhibits favourable drug-like properties, including compliance with Lipinski's rules, moderate CNS permeability, and a pharmacokinetic profile supportive of oral bioavailability. In vitro Parallel Artificial Membrane Permeability Assay (PAMPA) and microsomal stability studies revealed that TC9 exhibited high blood-brain barrier (BBB) permeability comparable to carbamazepine, while TC12 showed moderate permeability but was consistent with its predicted CNS penetration. Both TC analogues demonstrated favourable metabolic stability profiles in rat and human liver microsomes, supporting their potential for further pharmacological evaluation. Overall, TC12 represents a promising candidate for selective MAO-B inhibition.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"11203-11226"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029453","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":"Benchmarking docking and ML re-scoring screening performance for KRAS G12D in pancreatic cancer.","authors":"Ahmed R Elaraby, Mai I Shahin, Mahmoud M Elaasser, Mohammed T Elsaady, Ghada H Al-Ansary, Dalal A Abou El Ella, Tamer M Ibrahim","doi":"10.1007/s11030-026-11627-x","DOIUrl":"10.1007/s11030-026-11627-x","url":null,"abstract":"<p><p>The KRAS G12D mutation is commonly found in pancreatic cancer and is integral to the cell signaling pathway, making it a critical target for drug development. Structure-based virtual screening (SBVS) is a conventional strategy for discovering new inhibitors and expanding the chemical space against KRAS G12D. However, the SBVS efforts needed to be evaluated and benchmarked. Herein, in the first stage of the study, we evaluated two popular docking tools (FRED and AutoDock Vina) utilizing DeepCoy decoys-using DEKOIS 2.0 parameters-against KRAS G12D. Furthermore, re-scoring performance of the docking outcome via two popular pretrained machine learning scoring functions (ML SFs), such as CNN-Score and RF-Score-VS v2 were explored. While FRED exhibited the best screening performance based on pROC-AUC value, both tools showed high early enrichment indicated by EF 1%. Interestingly, both FRED and AutoDock Vina displayed superior performance to re-scoring using the ML SFs. This highlights the target-specific nature of the screening performance. In the second stage, accordingly, a VS effort was performed using FRED on specs world diversity database. Selected hits identified as potential KRAS G12D binders, were subjected to cell viability assays against the pancreatic cancer cell line PANC-1. Molecule (CP3) exhibited a promising antiproliferative activity with IC₅₀ value of 1.95 µM. Subsequently, molecular dynamics (MD) simulation and MM-GBSA calculations rationalized its postulated binding towards KRAS G12D. This study provides an example of how to conduct an in-depth benchmarking approach for KRAS G12D and offering an evaluated SBVS protocol for it.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"9745-9765"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337318","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, and biological evaluation of novel isobenzofuran-1(3H)-one derivatives with antioxidant properties and improved oral bioavailability.","authors":"Debasis Das, Kun Zhang, Lingzhi Xie, Yong Li, Yimeng Wu, Dandan Qiao, Yuxi Cao, Jianhe Jia, Jian Hong","doi":"10.1007/s11030-026-11637-9","DOIUrl":"10.1007/s11030-026-11637-9","url":null,"abstract":"<p><p>Bioavailability is a critical determinant factor of a drug, especially for its therapeutic efficacy, safety and commercial feasibility. Many active small molecule drugs suffer from poor oral bioavailability. 3-Butylisobenzofuran-1(3H)-one (NBP) is an approved small molecule agent by the CFDA for the treatment of acute cerebral ischemic stroke. NBP inhibits platelet aggregation, reduces brain infarct size, and attenuates ischemic-induced oxidative damage. However, the efficacy of NBP is limited due to its low bioavailability and high hydrophobicity. Sometimes, administration of high doses and increased frequency of NBP causes hepatotoxicity. Here, we designed, synthesized and evaluated a series of novel 6-substituted 3-butylisobenzofuran-1(3H)-one derivatives in vitro and in vivo and compared them with NBP or Br-NBP. Several compounds in the series showed better protective effects by preventing H₂O₂-induced LDH release and reduced ROS production in PC12 cells. In the in vivo pharmacokinetic study, compound 23 and compound 24 showed improved oral bioavailability and achieved F% = 52% and 44%, respectively. In addition, ADMET profiling and molecular docking simulations of 23 and 24 with MAO-A and MAO-B were conducted and the data included.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"9833-9852"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350218","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 network pharmacology and molecular modelling identify taxifolin as a potential modulator of melatonin receptor MT1 in mood disorders.","authors":"Shubham Singh Bartwal, Vishal Chhabra, Amita Rai, Krishna Murti, Nitesh Kumar","doi":"10.1007/s11030-026-11630-2","DOIUrl":"10.1007/s11030-026-11630-2","url":null,"abstract":"<p><p>Mood disorders are increasingly recognised as disorders of circadian dysregulation, with sleep abnormalities acting as both risk factors and clinical hallmarks. Despite extensive evidence linking circadian disruption to affective pathology, the precise molecular mechanisms remain incompletely defined. The present study aimed to identify shared genetic determinants of the sleep-circadian-mood axis and to discover natural neuromodulators that stabilise melatonergic signalling. Using an integrative network pharmacology and computational modelling approach, 644 overlapping genes across mood disorders, circadian rhythm, and insomnia were identified and mapped into protein-protein interaction networks. Functional enrichment revealed convergence on neuroinflammatory signalling (IL6, TNF, STAT3), circadian machinery (CLOCK, ARNTL, PER, CRY), and melatonergic signalling. Notably, melatonin receptors emerged as mechanistically coherent and clinically actionable GPCR targets, despite lower cluster scores relative to inflammation-dominant modules. Structure-based virtual screening of ~ 1,50,000 natural compounds against Melatonin 1 receptor identified taxifolin (- 9.527 kcal/mol) and tanshinone IIA (- 9.515 kcal/mol) as top candidates. Molecular dynamics simulations demonstrated that taxifolin formed highly stable protein-ligand complexes, characterised by sustained hydrogen bonding, reduced RMSD/RMSF fluctuations, and favourable interaction energetics. In contrast, tanshinone showed weaker hydrogen bonding, indicating higher ligand mobility. To provide preliminary biological validation, immunocytochemistry analysis was performed to assess the expression of circadian regulators (CLOCK and BMAL1 (ARNTL)) following treatment. Taxifolin modulated circadian protein expression in a manner comparable to melatonin, indicating an effect on cellular circadian signalling pathways. In conclusion, this study provides a systems-level framework linking circadian disruption, neuroinflammation, and mood pathology, while nominating taxifolin as a natural neuromodulator of melatonergic-associated pathways. These findings highlight taxifolin's translational potential as a safer alternative to synthetic melatonergic agents, representing a new direction in neurotherapy for mood disorders.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"9813-9832"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350257","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 novel cinnamic acid derivatives with anti-Helicobacter pylori mechanism.","authors":"Yonglian Li, Xiuya Ye, Yuan'e Yang, Wenfeng Liu, Suqing Zhao","doi":"10.1007/s11030-026-11651-x","DOIUrl":"10.1007/s11030-026-11651-x","url":null,"abstract":"<p><p>With the efficacy of standard anti-Helicobacter pylori (Hp) regimens declining due to increasing resistance and adverse effects, the development of safer alternatives is imperative. Inspired by the bioactivity of cinnamic acid, a series of cinnamic acid derivatives was designed and screened for their activity against Hp. Among the synthesized derivatives, compound 23, bearing a dinitro group, exhibited potent anti-Hp activity with a minimum inhibitory concentration (MIC) of 4 µM, demonstrating a two-fold greater potency than metronidazole. Meanwhile, the quinoline-containing derivative (compound 25) showed activity comparable to that of metronidazole. Compound 23 was highly specific for Hp, showing no efficacy against other gastrointestinal pathogens (MIC > 128 µM). The mechanistic studies indicated that compound 23 could cause severe cellular damage (vesicle formation, swelling, and plasmolysis), disrupt biofilms, and inhibit urease, thereby blocking ammonia cloud formation. Furthermore, it effectively suppressed the production and the overexpression of inflammatory mediators in RAW264.7 cells. Therefore, these results suggested that compound 23 was a viable lead candidate for the treatment of Hp infection.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"9943-9959"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389783","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":"Integrated deep learning and multi-scale modeling for the discovery of pan-genotypic HCV NS5B polymerase inhibitors.","authors":"Di Han, Fengxiang Liu, Xiangbing Peng, Yifan Wang, Zhipeng Shi, Yiwei Xue, Hongkun Yang, Meiting Wang, Jiarui Lu, Taigang Liu, Shaoli Cui, Yongtao Xu","doi":"10.1007/s11030-026-11633-z","DOIUrl":"10.1007/s11030-026-11633-z","url":null,"abstract":"<p><p>Chronic Hepatitis C Virus (HCV) infection remains a significant global health challenge, necessitating the development of pan-genotypic inhibitors to overcome the limitations of genotype-specific therapies. The NS5B RNA-dependent RNA polymerase, particularly its conserved Palm II region, is a promising target for such broad-spectrum antivirals. In this study, we integrated advanced deep learning and multi-scale computational approaches to design novel pan-genotypic HCV NS5B inhibitors. First, we employed AlphaFold3 to predict the high-resolution structures of NS5B polymerase from genotypes with previously unresolved crystal structures (GT3a, GT3b, GT6a, GT7a, and GT8a), establishing a robust structural database refined by 100 ns molecular dynamics (MD) simulations. Concurrently, the DrugEx algorithm, a multi-objective reinforcement learning-based molecular generator, was used for de novo design, yielding 42,257 novel chemical entities. Subsequent multi-step virtual screening, molecular docking, and 300 ns MD simulations identified four hit compounds (01, 07, 18, 59) that demonstrated promising computational binding profiles and pan-genotypic coverage compared to the positive control BMS-986,139. These compounds exhibited excellent stability in complex with NS5B across ten genotypes, as evidenced by low RMSD fluctuations. MM/GBSA binding free energy calculations and hydrogen bond analysis revealed key interaction mechanisms, including dynamic hydrogen bonding with Tyr448 and strong electrostatic contributions from Arg200, which underpin their broad-spectrum efficacy. Furthermore, ADMET predictions confirmed favorable drug-like properties and synthetic feasibility, supported by retrosynthetic analysis. This work presents a comprehensive \"AlphaFold3-DrugEx-Multi-scale Simulation\" strategy, enabling the efficient discovery of novel, potent, and pan-genotypic HCV NS5B inhibitors candidates with significant potential for further development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10103-10131"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417615","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}