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{"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":"New 3H-1,2-Dithiole-3-thione derivatives: Design and synthesis, H₂S-release profile, in vitro anticancer activity, and in silico multi-target assessment.","authors":"Semra Altunsoy, Yakup Berkay Yılmaz, Tuğba Güngör, Hazal Nazlıcan Atalay, Mine Isaoğlu, Serdar Durdağı, Mehmet Ay, Tugba Boyunegmez Tumer","doi":"10.1007/s11030-026-11635-x","DOIUrl":"10.1007/s11030-026-11635-x","url":null,"abstract":"<p><p>Cancer continues to be a leading cause of global mortality, highlighting the ongoing need for novel anticancer compounds that offer high efficacy with improved side effect profiles. In the present study, a series of 3H-1,2-dithiole-3-thione derivatives (DTT-S1-18) were synthesized as promising anticancer agents, and the structures of products were confirmed by spectral techniques. H₂S-releasing experiments showed that most of the compounds released higher amounts of H₂S slowly over time compared to standard ADT-OH. All compounds were tested for antiproliferative activity on HT-29, PC-3, MCF-7, and HUVEC cell lines. Compounds DTT-S6 (3-nitrophenyl derivative) and DTT-S8 (methionine derivative) have the lowest IC₅₀ values of 41.6 and 38.9 µM on the MCF-7 cell line, respectively. Based on the wound healing and colony formation assays performed in MCF-7 cells, the wound areas were not significantly changed after treatment with compounds DTT-S6 and DTT-S8, whereas compound DTT-S8 at double IC₅₀ dose inhibited colony formation by 81.82%. In addition, molecular docking, MD simulations, MM/GBSA binding free energy calculations, and binary QSAR analyses were performed to explore the potential target interactions and predicted activity profiles of the synthesized compounds toward inflammation-related proteins, including COX-1, COX-2, 5-LOX, and iNOS, thereby supporting the development of mechanistic hypotheses for future validation. Furthermore, structure-activity relationship (SAR) analyses were conducted to correlate the structural characteristics of the synthesized compounds with their H₂S releasing potential and biological profiles. Overall, this work integrates experimental anticancer evaluation with computational pathway and structure-based cancer/inflammation analyses to characterize novel DTT-based H₂S donors. The findings identify particularly compound DTT-S8, as a promising in vitro anticancer candidate, while the computational results suggest a putative involvement of inflammation-related targets, particularly the COX-2/5-LOX axis, which requires direct biochemical and cellular validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10387-10416"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel serotonin transporter (SERT) inhibitors via large-scale machine learning-based virtual screening and molecular dynamics simulations.","authors":"Rujia Zhao, Tianzhu Shen, Tongzhou Huang","doi":"10.1007/s11030-026-11705-0","DOIUrl":"10.1007/s11030-026-11705-0","url":null,"abstract":"<p><p>The serotonin transporter (SERT) plays a pivotal role in inflammatory responses and is a central therapeutic target for depression. Consequently, identifying potent SERT inhibitors remains a high priority in early-stage drug discovery. In this study, we evaluated twelve regression models, among which LightGBM, Random Forest, and XGBoost exhibited superior predictive performance, yielding R² values of 0.7138, 0.7001, and 0.6920, respectively. Leveraging these optimized machine learning models, we conducted a large-scale virtual screening of over 11.5 million compounds, identifying 24 promising candidates. Subsequent molecular dynamics (MD) simulations and MM/GBSA binding free energy calculations supported the structural stability and strong predicted binding affinities of three lead molecules: Z2215663922, 19,835,875, and Z310319934. Furthermore, ADMET profiling indicated generally acceptable pharmacokinetic properties, although potential hERG-related liabilities for certain candidates warrant further experimental scrutiny. Our findings provide structurally diverse scaffolds and a computational prioritization framework for early-stage discovery and optimization of SERT inhibitor candidates that merit subsequent experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10755-10769"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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}