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{"title":"Design, synthesis and biological evaluations of novel VEGFR-2 inhibitors based on Fruquintinib and Cabozantinib.","authors":"Xueyan Ding, Heliang Wei, Mengling Ye, Yudan Huang, Aike Su, Xiaoying Ding, Wenfa Chen, Zhaosheng Tang, Junjie Ma","doi":"10.1007/s11030-026-11628-w","DOIUrl":"10.1007/s11030-026-11628-w","url":null,"abstract":"<p><p>In this study, two series of VEGFR-2 inhibitors were designed based on the Fruquintinib and Cabozantinib. Series 1 compounds retained the quinazoline skeleton and amide group of Fruquintinib, while the benzofuran moiety was replaced with a coumarin moiety, and various substituents were introduced at the amide N-terminus to explore structure-activity relationships (SARs). Series 2 compounds were derived from Cabozantinib by incorporating a rigid pyridine linker via conformational constraint and replacing the terminal phenyl group with bicyclo[1.1.1]pentane (BCP). All target compounds were evaluated for their VEGFR-2 inhibitory activity. Among series 1, compound 20 showed the significant inhibitory activity with an IC₅₀ value of 85.35 nM. Notably, series 2 compounds demonstrated significantly improved potency, with IC₅₀ values below 30 nM. Compound 32 was the most potent VEGFR-2 inhibitor with an IC₅₀ value of 7.52 nM, while its IC₅₀ values for VEGFR-1 and VEGFR-3 were 74.41 and 5.63 nM, respectively. In vitro antiproliferative assays revealed that several series 2 compounds, including 32, displayed more potent antiproliferative activity against A549 cells than Cabozantinib. Molecular docking studies elucidated the binding mode of compound 32, highlighting key hydrogen bond with the hinge region of VEGFR-2. Collectively, compound 32 emerges as a promising lead compound for further optimization as a novel VEGFR-2 inhibitor.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"9791-9812"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350244","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 anti-prostate cancer activity evaluation of novel thieno[2,3-b]pyridine derivatives as potential BLM helicase inhibitors.","authors":"Wei Tu, Ningning Zan, Xinyu Liu, Gang Yu, Xiaoping Zeng, Yafang Zhou, Jia Yu, Xueling Meng, Kun Liu, Xiaolin Peng, Sha Cheng, Bixue Xu, Guangcan Xu","doi":"10.1007/s11030-026-11649-5","DOIUrl":"10.1007/s11030-026-11649-5","url":null,"abstract":"<p><p>Herein, twenty-four novel thieno[2,3-b]pyridine derivatives were rationally designed and synthesized based on a versatile key intermediate. All compounds were evaluated for in vitro antiproliferative activity against PC3 and VCaP prostate cancer cell lines using the MTT assay, and most exhibited good antitumor potency. Compound 9v showed the strongest activity, with IC₅₀ values of 0.49 μM (PC3) and 0.85 μM (VCaP). Mechanistic studies revealed that 9v concentration-dependently induced apoptosis and G0/G1 cell cycle arrest, and suppressed PCa cell migration and invasion in both time- and concentration-dependent manners. Further target validation showed that 9v efficiently inhibited BLM helicase-mediated DNA unwinding with an IC₅₀ of 3.17 μM, outperforming the lead compound TC1. Combined MST and BLI assays verified that 9v exhibited higher binding affinity toward BLM protein than the lead compound TC1 and preferentially interacted with BLM instead of its DNA substrate. Mechanistically, 9v competitively interfered with BLM-DNA substrate interaction to block BLM DNA unwinding function. Molecular docking revealed that 9v stably bound to key amino acid residues in the BLM RQC domain, consistent with the binding characteristics of reported BLM inhibitors. In conclusion, 9v displays superior antiproliferative and BLM helicase inhibitory activities compared with TC1, representing a promising lead compound for the development of novel BLM-targeted anti-prostate cancer agents.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10019-10048"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410100","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 machine learning and structural bioinformatics guided identification of novel molecular scaffolds as renin inhibitors.","authors":"Shubham Krushna Talware, Girdhar Bhati, Gaurava Srivastava, Sarvbhaum Shukla, Shakil Ahmed, Mohammad Imran Siddiqi","doi":"10.1007/s11030-026-11676-2","DOIUrl":"10.1007/s11030-026-11676-2","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) remain the leading cause of death globally, with hypertension as its critical hallmark. The Renin-Angiotensin-Aldosterone-System (RAAS) plays a central role in regulating blood pressure, highlighting its relevance for antihypertensive drug development. Despite extensive research, Aliskiren remains the only clinically approved direct renin inhibitor (DRI), underscoring the necessity for novel scaffolds with improved pharmacokinetic profiles. In this study, we employed an integrated machine learning (ML), ligand-based (LBDD), and structure-based drug design (SBDD) approach to identify and characterize new chemical scaffolds with potential renin inhibitory activity. Multiple ML models were built using various molecular descriptors, followed by extensive feature selection, and data balancing with SMOTE. To enhance model interpretability, we performed SHAP analysis on the top ML models to reveal key descriptors and substructures associated with predictions for renin inhibition. In parallel, several ligand-based pharmacophore models were constructed using the crystal structure of human renin. Maybridge library was screened using the best models resulting from both approaches, and the consensus compounds were prioritized using molecular docking to assess their inhibitory potential through the renin inhibitory assay. Molecular dynamics, along with MM/PBSA, were then employed to evaluate the structural stability and binding persistence of the screened compounds with promising activity. The predicted ADME properties and structural analysis further established the relevance of the novel scaffolds identified through our robust integrated approach. From the 12 shortlisted compounds, our study identified 4 promising hits - HTS00804, HTS05294, BTB13902, and RJC01726 with diverse piperazine and piperidine-substituted scaffolds for renin inhibition. All four hits exhibited IC50 values between 1.29 µM and 4.19 µM. Among all, HTS00804 demonstrated 53 and 73% renin inhibition in vitro at 1µM and 10 µM concentrations, respectively and can be explored as a starting scaffold for further structural optimization through medicinal chemistry efforts to design next-generation direct renin inhibitors (DRIs).</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10361-10386"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560519","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":"Synthesis and antifungal activity evaluation of flavonol derivatives containing an imidazolidinone moiety.","authors":"Qingxue Hu, Xiaoting Geng, Xiaoyan Pan, Dan Shen, Han Yang, Fang Tian, Mingman Sun, Lang Xing, Ying Yang, Wei Xue","doi":"10.1007/s11030-026-11687-z","DOIUrl":"10.1007/s11030-026-11687-z","url":null,"abstract":"<p><p>Phytopathogenic fungi pose a major threat to crop production and food safety, driving an urgent need for novel, highly effective, and environmentally friendly antifungal agents. To address this need, 22 flavonol derivatives incorporating imidazolidinone pharmacophore were designed and synthesized, and their antifungal activities were systematically evaluated against seven plant pathogenic fungi. Among them, H7 was selected as a candidate compound due to its superior activity, exhibiting a half-maximal effective concentration (EC₅₀) value of 10.1 μg/mL against Phomopsis sp., superior to the reference fungicides azoxystrobin (Az: EC₅₀ = 38.0 μg/mL) and fluopyram (Fl: EC₅₀ = 177.3 μg/mL). In vivo assays on kiwifruit demonstrated that at 200 μg/mL, H7 provided curative and protective efficacies of 60.5 and 67.1%, respectively, both superior to those of Az (39.5 and 44.0%). Preliminary mechanistic investigations suggested that the antifungal activity of H7 is associated with disruption of cell membrane integrity and inhibition of succinate dehydrogenase activity. Collectively, these findings indicate that H7 could serve as a lead compound for the development of novel fungicides against kiwifruit soft rot.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10503-10522"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688334","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-guided QSAR screening of fluconazole analogs and FDA-approved drugs against Candida albicans, with docking, molecular dynamics, and ADMET analysis.","authors":"Hamza Age Daudo, Emmanuel Silva Marinho, Victor Moreira de Oliveira, Márcia Machado Marinho, Ribeiro Vasco Ribeiro","doi":"10.1007/s11030-026-11621-3","DOIUrl":"10.1007/s11030-026-11621-3","url":null,"abstract":"<p><p>Invasive candidiasis caused by Candida albicans is a critical-priority fungal disease associated with high mortality, and the increasing resistance to fluconazole underscores the urgent need for new antifungal agents. In this study, a machine learning (ML)-guided quantitative structure-activity relationship (QSAR) workflow was developed to prioritize fluconazole analogs and FDA-approved drugs with predicted antifungal activity against Candida, followed by a structure-based exploration of a cell wall target. Bioactivity (IC₅₀) data for the CHEMBL366 target were curated to 1000 compounds, encoded using Morgan fingerprints (ECFP4, 2048 bits), and used to benchmark 42 regression algorithms; the three best-performing tree ensemble models (Extra Trees, Gradient Boosting, and Bagging) were optimized with Optuna. The Extra Trees model achieved the best performance (test R² = 0.70; RMSE = 0.38), and the applicability domain (AD) covered approximately 93% of the test compounds. Consensus virtual screening of fluconazole analogs from the ZINC database and 1683 FDA-approved drugs prioritized two structurally related analogs (ZINC000299869729 and ZINC000299869730). Molecular docking against exo-β-(1,3)-glucanase (PDB ID: 1EQP), used as an exploratory mechanistic hypothesis, produced more favorable scores (- 9.1 to - 9.6 kcal/mol) than fluconazole (- 8.5 to - 8.9 kcal/mol). In 200 ns molecular dynamics simulations, ZINC000299869730 showed greater conformational stability, while ZINC000299869729 exhibited the most favorable MM/GBSA binding free energy (- 19.02 kcal/mol). pkCSM-based ADMET profiling predicted good intestinal absorption but also shared AMES mutagenicity and hepatotoxicity alerts, which would require mitigation through structural optimization. All findings are strictly in silico and require experimental validation of antifungal activity and safety.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10487-10502"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688377","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":"Addressing the selectivity challenge in matrix metalloproteinases: fragment-based design of MMP-9 inhibitors targeting the S1' pocket.","authors":"Ashish Kumar, Md Sameer, Arbaz Sujat Shaikh, Yaman Chauhan, Venkata Rao Kaki","doi":"10.1007/s11030-026-11723-y","DOIUrl":"10.1007/s11030-026-11723-y","url":null,"abstract":"<p><p>Matrix metalloproteinase-9 (MMP-9) plays a pivotal role in extracellular matrix remodelling and is strongly implicated in tumour progression, metastasis, and angiogenesis, making it an attractive therapeutic target for anticancer drug discovery. However, the development of potent and selective MMP-9 inhibitors has been significantly hampered due to the high structural homology among members of the MMP family, particularly within the catalytic domain. Structural studies revealed a non-conserved S1' pocket of MMP-9 exhibits distinct structural variability compared to other MMP isoforms, providing an opportunity to achieve improved selectivity. To the best of our knowledge, fragment-based drug design (FBDD) approaches specifically targeting the S1' pocket of MMP-9 have not been systematically explored. In the present study, an integrated in silico FBDD workflow was employed to identify and optimize small molecules occupying the S1' pocket of MMP-9. Initial fragment-based virtual screening identified low-molecular-weight fragments with moderate binding affinity toward the target pocket. A promising fragment hit was subsequently optimised through a receptor cavity-guided fragment-growing strategy to extend interactions toward residues in the neighbouring S2' pocket. Induced-fit docking analysis identified several optimized molecules with enhanced binding affinity and favourable orientation within the S1' pocket. The stability of the protein-hit molecule complexes was further validated through 200 ns molecular dynamics simulations, which confirmed stable binding interactions for four molecules. Comparative docking and MM-GBSA analyses against MMP isoforms demonstrated a preferential affinity of hit molecules for MMP-9, suggesting a potential selectivity profile driven by ligand binding free energy and orientation in S1' pocket. In addition, in silico ADME profiling indicated favourable pharmacokinetic properties of all the stable hit molecules, while density functional theory studies helped to gain insights into the electronic distribution and reactivity of the molecules. Collectively, this study establishes an in silico framework for the structure-based design of potentially selective MMP-9 inhibitors targeting the non-conserved S1' pocket.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"11065-11092"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918007","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 a new SARS-CoV-2 Mpro inhibitor from a natural product and natural product-like compound database using in silico and in vitro studies.","authors":"Sudesna Das, Uttam Pal, Yasmin Begum, Akshay Joshi, Nittu Singh, Krishan Gopal Thakur, Umesh Prasad Singh","doi":"10.1007/s11030-026-11724-x","DOIUrl":"10.1007/s11030-026-11724-x","url":null,"abstract":"<p><p>This current study employs structure-guided virtual screening to identify potential inhibitors from 69,075 natural product or natural product-like compounds in the InterBioscreen (IBS) database against the SARS-CoV-2 Main protease (Mpro), a well-validated target. From high-throughput structure-guided virtual screening, subsequently followed by more rigorous re-docking, top seven compounds were chosen as hits based on their high binding affinity and specific H-bond interactions with the active-site residues of Mpro. All these compounds were new for this target as well as the virus. The stability of the seven protein-ligand complexes was further assessed using molecular dynamics (MD) simulations and the MM-GBSA method. The ADME/Tox profile of these seven compounds was also predicted theoretically. After MD simulation, only three compounds, viz. STOCK1N-86169, STOCK1N-88750, and STOCK1N-65657 were identified as high-potential candidates for Mpro inhibition. To confirm the in silico analysis results, an in vitro FRET-based Mpro inhibition assay and an ELISA-based SARS-CoV-2 inhibition assay were performed. From these in vitro investigations, STOCK1N-86169 was identified as the only potent Mpro inhibitor, exhibiting an IC₅₀ of 3.8 µM. Independent confirmation of STOCK1N-86169 binding to Mpro was obtained by differential scanning calorimetry (DSC), which revealed an increase of approximately 15 °C in the melting temperature (Tm) of the Mpro-STOCK1N-86169 complex relative to the apo-protein. In the cytotoxicity assay, it showed CC₅₀ > 100 µM for HeLa, ~ 100 µM for the Huh-7 cell line, and ~ 33.5 µM for the Vero E6 cell line. In the Vero cell-based SARS-CoV-2 infection assay, it showed an EC₅₀ of ~ 7 µM, with a reasonable Selective Index (S.I.) of ~ 5-fold. Our study suggests that the natural product like compound STOCK1N-86169, which presents a new scaffold for Mpro inhibition and also SARS-CoV-2, may be a promising candidate for further development as an effective inhibitor of SARS-CoV-2 Mpro.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"11177-11202"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029408","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":"Synthesis, ¹³¹I-radioiodination, and biodistribution of a novel nicotinonitrile derivative with in vitro antimicrobial and DNA gyrase inhibitory activities.","authors":"Basant G Salib, Basma M Essa, Hesham A Shamsel-Din, Mohamed A Motaleb, M El-Tawoosy, Adli A Selim, Sameh Ahmed Rizk, Ahmed Hassan Ibrahim Faraag, Mohamed A Ali, Islam Yousif Mostafa, Reda Mansour, Salah S Elyan, Mohamed Salah Basiouny, Kurls E Anwer","doi":"10.1007/s11030-026-11661-9","DOIUrl":"10.1007/s11030-026-11661-9","url":null,"abstract":"<p><p>To address the rise of multidrug-resistant bacteria by developing novel antibacterial agents with integrated capabilities for targeted delivery and real-time tracking, and to evaluate their potential for infection theranostics. Novel enaminonitrile-based pyridine and pyran derivatives were sustainably synthesized. Among them, lead compound 5 was assessed for in vitro DNA gyrase inhibition. Compound 5 was then radiolabeled with iodine-131, and radiolabeling yield was measured. In vivo biodistribution and pharmacokinetic profile were evaluated using an inflammatory murine model, with target-to-muscle ratios calculated. Compound 5 showed potent DNA gyrase inhibition (IC₅₀ = 11.31 µg/mL). Radiolabeling produced [¹³¹I]I-5 with high radiolabeling yield (90.15%). In the murine model, the radiolabeled construct demonstrated rapid blood clearance and sustained, specific accumulation at the infection site, achieving a high target-to-muscle ratio of 5.18 at 1-h post-administration. This study introduces a new class of antibacterial agents and successfully translates a lead compound into a theranostic formulation. [¹³¹I]I-5 shows strong promise as a candidate for image-guided therapy and targeted treatment of infectious diseases.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10323-10340"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into the structure-activity relationships of flavonoids targeting WSSV and LvGSTMu.","authors":"Damião Sampaio de Sousa, João Miguel Lopes de Melo Lima, Jacilene Silva, Márcia Machado Marinho, Emmanuel Silva Marinho","doi":"10.1007/s11030-026-11673-5","DOIUrl":"10.1007/s11030-026-11673-5","url":null,"abstract":"<p><p>White spot syndrome virus (WSSV) represents one of the most severe threats to shrimp aquaculture worldwide, with no effective antiviral treatments currently available. In this study, the antiviral and antioxidant potential of the flavonoids amentoflavone, agathisflavone, and apigenin was investigated using an integrated in silico approach combining molecular docking, pharmacophore analysis, and Normal Mode Analysis (NMA)-based molecular dynamics. Docking simulations revealed that all flavonoids bind favorably to WSSV thymidylate synthase (wTS) and to the glutathione S-transferase from L. vannamei (LvGSTmu), with binding affinities superior to those of the co-crystallized ligands. Amentoflavone showed the highest affinity toward wTS, preserving key catalytic interactions and closely mimicking the binding mode of the native substrate. Pharmacophore analysis highlighted the importance of aromatic centers and hydrogen bond donor/acceptor groups in stabilizing ligand-protein complexes. NMA-based dynamics demonstrated that amentoflavone and apigenin confer increased structural stability to wTS and LvGSTmu, respectively, reducing conformational fluctuations without compromising protein integrity. Molecular dynamics simulations confirmed the stability of the complexes throughout the 200 ns simulation, while MM/GBSA analysis revealed favorable binding free energies, supporting stable interactions with wTS. Overall, these results suggest that flavonoids, particularly amentoflavone, represent promising scaffolds for the development of antiviral and antioxidant agents against WSSV, warranting further experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10431-10451"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617880","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":"ARG128-associated recognition of nobiletin by BACE1 revealed by triplicate molecular dynamics, MM-GBSA, and residue-level decomposition.","authors":"Zihan Wang, Jing Chen","doi":"10.1007/s11030-026-11693-1","DOIUrl":"10.1007/s11030-026-11693-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and beta-secretase 1 (BACE1) remains a high-priority target for reducing amyloid-beta production. Nobiletin, a polymethoxylated flavonoid from citrus peel, has reported neuroprotective and amyloid-lowering effects in AD models, and previous enzymatic work suggested weak BACE1 inhibition; however, its replica-level binding stability and residue-level energetic determinants remain unresolved. Here, we analyzed the nobiletin-BACE1 complex using ChEMBL-based chemical-space contextualization, qualitative QSAR uncertainty assessment, molecular docking, triplicate 200-ns all-atom molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) end-point scoring, residue-level decomposition, ProLIF interaction fingerprints, electrostatic surface analysis, and a same-protocol OM99-2 structural control. The ligand remained locally accommodated within the BACE1 cleft across the sampled trajectories, with a mean internal MM-GBSA score (DeltaG_bind) of - 15.71 +/- 0.76 kcal/mol (n = 3: - 14.20, - 16.35, and - 16.57 kcal/mol). Residue-level decomposition identified ARG128 as the dominant computed hotspot (total mean = - 11.13 +/- 0.38 kcal/mol), with favorable van der Waals (VDW mean = - 6.88 +/- 0.21 kcal/mol) and Coulombic (Coulomb mean = - 4.25 +/- 0.53 kcal/mol) components. Additional hydrophobic/aromatic packing involved VAL69, TYR71, PRO70, PHE38, and PRO129, while ASP32/ASP228 were positioned outside the dominant nobiletin contact pattern. Together, these results support a putative ARG128-associated, non-dyad-dominant catalytic-cleft recognition model that should be interpreted as a hypothesis-generating computational framework for future biochemical testing and scaffold optimization.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"10531-10546"},"PeriodicalIF":4.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688347","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}