Molecular Diversity最新文献

{"title":"Lipase ITB 2.1: a structure- and function-validated model for anti-obesity drug screening.","authors":"Ilma Fauziah Ma'ruf, Teni Ernawati, Faris Hermawan, Akhmaloka Akhmaloka, Fida Madayanti Warganegara, Made Puspasari Widhiastuty, Elvi Restiawaty, Hesti Lina Wiraswati, Ahmad Wibisana, Tjandrawati Mozef, Nur Akmalia Hidayati, Titin Haryati, Dimas Frananta Simatupang","doi":"10.1007/s11030-026-11731-y","DOIUrl":"https://doi.org/10.1007/s11030-026-11731-y","url":null,"abstract":"<p><p>Lipases are key enzymes in lipid metabolism and represent important therapeutic targets for obesity and metabolic disorders. This study integrates sequence analysis, structural modelling, molecular docking, molecular dynamics simulations, and enzymatic assays to elucidate evolutionary conservation and the inhibitory mechanism of orlistat against lipase ITB 2.1. Multiple sequence alignment revealed strong conservation of catalytic serine residue at the nucleophilic elbow across bacterial, fungal, and mammalian lipases, with rare AXSXG motif substitutions in Bacillus and Geobacillus species, indicating adaptive structural variation. Phylogenetic and distance analyses demonstrated clear evolutionary clustering while revealing unexpected relationships among mammalian, fungal, and bacterial lipases, suggesting functional convergence. Superimposition of 3-dimensional structure confirmed preservation of the α/β-hydrolase fold and highlighted lid-dependent conformational changes that regulate active-site accessibility. Molecular docking showed substantially stronger binding of orlistat to the open-lid conformation than to the closed state, with lipase ITB 2.1 exhibiting the most favourable binding affinity among the analysed enzymes. Molecular dynamics simulations (100 ns) confirmed stable ligand-enzyme complexes, with monoacylglycerol lipase and pancreatic lipase displaying the highest structural stability, while lipase ITB 2.1 maintained consistent compactness and ligand retention. Enzymatic inhibition assays experimentally validated the computational predictions, demonstrating kinetic value with Vmax 1428 µM/min; Km 81 µM and complete inhibition at 56.25 µM orlistat. Collectively, these findings establish lipase ITB 2.1 as a robust model for lipase inhibition and drug screening studies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954641","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":"Correction: Identification and validation of natural dengue virus NS1 inhibitors with promising antiviral potential.","authors":"Hanaan Kasim Ansari, Alisha, Mirza Sarwar Baig, Aquib Reza, Prem Prakash, Mairaj Ahmed Ansari, Anuja Krishnan","doi":"10.1007/s11030-026-11715-y","DOIUrl":"https://doi.org/10.1007/s11030-026-11715-y","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954678","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":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","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":"Computational discovery of novel human rhinovirus 3 C protease inhibitors: molecular docking, dynamic simulations, free energy landscape, MMPBSA and ADMET analysis.","authors":"Hafs Essaadi, Abdelfateh Chourir, Jouhaina Kourou, Farah Makhloufi, Ouissal Hachlaf, Aya Abidou, Saber Boutayeb, Rachid Eljaoudi, Lahcen Belyamani, Azeddine Ibrahimi, Mohammed Hakmi, Naima El Hafidi","doi":"10.1007/s11030-026-11704-1","DOIUrl":"https://doi.org/10.1007/s11030-026-11704-1","url":null,"abstract":"<p><p>Human rhinoviruses (HRVs) are major causative agents of the common cold and are strongly associated with asthma exacerbation, highlighting the need for effective antivirals. Because the viral 3 C protease (3Cpro) is essential for polyprotein processing and is highly conserved among HRV species, it represents an attractive therapeutic target. In this study, we performed structure-based virtual screening of 49,437 compounds against HRV-C 3Cpro using AutoDock Vina, followed by ADMET-based prioritization of the top hits. Docking analysis identified two lead compounds that favorably occupied the catalytic pocket and formed stabilizing interactions with key residues, including His40, Glu71, and Cys147, in comparison with the reference inhibitor rupintrivir. In 200-ns molecular dynamics simulations, both compounds stabilized the protease relative to the apo form, with compound 1 showing the lowest protein RMSD (1.21 ± 0.22 Å) and compound 2 producing the lowest Cys147 RMSF (0.48 Å). Both ligands also displayed lower ligand RMSD values than rupintrivir (compound 1: 1.49 ± 0.78 Å; compound 2: 2.01 ± 0.39 Å; rupintrivir: 4.83 ± 0.89 Å), indicating more persistent binding within the active site. MM/PBSA analysis further supported stronger effective binding for compound 1 (-23.59 ± 6.87 kcal/mol) and compound 2 (-25.25 ± 5.75 kcal/mol) than for rupintrivir (-19.43 ± 4.46 kcal/mol). Taken together, these results identify compounds 1 and 2 as promising non-covalent HRV 3Cpro inhibitor candidates for further experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917960","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":"Hot spot-driven discovery of β-catenin/Tcf4 interaction inhibitors via virtual drug repurposing study and experimental validation in colorectal cancer cells.","authors":"Kader Sahin, Ajda Coker, Serdar Durdağı","doi":"10.1007/s11030-026-11720-1","DOIUrl":"https://doi.org/10.1007/s11030-026-11720-1","url":null,"abstract":"<p><p>Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer, primarily driven by the interaction between β-catenin and T-cell factor 4 (Tcf4). Due to the large and shallow interface (~ 4800 Ų) of this protein-protein interaction, it has historically been considered \"undruggable.\" However, emerging evidence highlights the presence of druggable hot spots within this interface. In this study, we employed a structure-based virtual screening approach to repurpose FDA-approved drugs targeting the β-catenin/Tcf4 interaction. Using physics-based molecular simulations and MM/GBSA binding free energy calculations, we identified Leucovorin (Folinic acid), Carbenicillin, and Ceforanide as promising candidate hit compounds with stable binding to critical hot spot residues (Asn430, Lys435, His470, Arg474, and Lys508) of β-catenin. Experimental validation using HT-29 colorectal cancer cells revealed that Carbenicillin and Ceforanide reduced the cell viability, impaired the colony formation, and exhibited superior anti-proliferative activity compared to the other candidates. These findings provide compelling evidence for the feasibility of targeting β-catenin/Tcf4 interactions using small molecules and suggest that Carbenicillin and Ceforanide may serve as promising repurposed candidates for therapeutic intervention in Wnt-driven malignancies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917675","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":"Molecular-networking-based characterization of cytotoxic metabolites produced by the cyanobacterium Nostoc edaphicum CCNP1411.","authors":"Robert Konkel, Marta Cegłowska, Łukasz Grabowski, Wiktoria Jeleniewska, Monika Zielenkiewicz, Katarzyna Gonera, Grzegorz Węgrzyn, Hanna Mazur-Marzec","doi":"10.1007/s11030-026-11717-w","DOIUrl":"https://doi.org/10.1007/s11030-026-11717-w","url":null,"abstract":"<p><p>Cyanobacteria of the genus Nostoc, known for their large genomes and rich repertoire of biosynthetic gene clusters, represent a prolific source of structurally diverse secondary metabolites with diverse biological activities, including cytotoxic effects. However, the identification of bioactive compounds is often hindered by low metabolite abundance and difficulties in isolating sufficient quantities for individual testing. In this study, we investigated the cytotoxic potential of chromatographic fractions obtained from Nostoc edaphicum CCNP1411 using a combination of bioassay-guided fractionation and LC-MS/MS-based feature-based molecular networking (FBMN). Cytotoxic activity was evaluated using the MTT assay across a panel of epithelial and neuronal cancer cell lines, as well as normal human dermal fibroblasts. The most active fractions, eluted with 80-90% MeOH, exhibited broad cytotoxic effects across all tested cancer cell lines. Molecular networking analysis revealed that these fractions were dominated by lipid derivatives, including lysophospholipids, monoacylglycerols, and free fatty acids, whereas previously described peptide metabolites were distributed across all fractions and were unlikely to be the main agents responsible for the observed activity. Targeted testing of selected commercially available lipid compounds confirmed their cytotoxic effects, with lysophospholipids showing the highest potency in selected cell lines. However, dose-response analysis indicated that most compounds exhibited limited potency at lower concentrations, as reflected by relatively high IC₅₀ values. Overall, our results demonstrate that lipid constituents, previously overlooked as bioactive metabolites produced by N. edaphicum CCNP1411, contribute significantly to the cytotoxic activity of the tested fractions. The application of molecular networking enabled the prioritization of bioactive metabolites and highlights its utility in linking chemical composition with biological effects in complex cyanobacterial extracts.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917747","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":"Electrochemical synthesis of antioxidant trideuteromethylthiolated enaminones through three-component cascade reactions.","authors":"Jingjing Wang, Lijin Wang, Wenbo Zhang, Yaping Liu, Daoyong Ni, Ge Wu, Yuedan Wu","doi":"10.1007/s11030-026-11732-x","DOIUrl":"https://doi.org/10.1007/s11030-026-11732-x","url":null,"abstract":"<p><p>An NH₄I-mediated electrochemical three-component cascade reaction has been established for the preparation of trideuteromethylthiolated enaminones from primary amines, acetylacetone, and CD₃SSO₃Na. This simple protocol is readily applicable to gram-scale synthesis and late-stage modification of bioactive molecules. Preliminary biological screening of the prepared trideuteromethylthiolated enaminones identified compound 4l is capable of protecting cells from oxidative damage by initiating the activation of the Nrf₂/HO-1 signaling pathway.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917691","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 of dual PROTACs for potential therapeutic applications.","authors":"Shun-Ran Li, Meng-Qian Yu, Bo-Qun Du, Ke-Jun Jin, Shu-Xun Chen, Zi Hui, Hang Zhang, Nian-Dong Mao, Yuan Gao, Xiang-Yang Ye","doi":"10.1007/s11030-026-11734-9","DOIUrl":"https://doi.org/10.1007/s11030-026-11734-9","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has revolutionized drug discovery, with PROTACs leading the charge by catalytically eliminating disease-causing proteins. While conventional PROTACs degrade a single target, the complexity of diseases like cancer and neurodegeneration-marked by redundant and compensatory signaling networks-has spurred the rapid development of dual/multi-target PROTACs capable of simultaneously degrading two or more pathogenic proteins. This review systematically surveys recent advances (2023-2026) in this area, categorizing them into two classes: those targeting homologous proteins (e.g., CDKs, BCL-2/BCL-xL, HDACs, BAZ2A/BAZ2B) and those targeting distinct proteins across interconnected pathways (e.g., ERα/ARO, α-Syn/tau, BET/HDAC, PI3K/mTOR, FLT3/CHK1, CBP/BRD4, and others). For each, we critically analyze design strategies, structure-activity relationships, linker optimization, and E3 ligase selection. Despite remarkable progress-including the first dual degraders for non-kinase epigenetic regulators and protein aggregates-challenges persist in pharmacokinetics, off-target toxicity, and limited E3 ligase diversity. By consolidating key breakthroughs and practical SAR insights, this review provides a valuable resource for advancing next-generation multi-target degraders toward clinical translation for complex diseases.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917694","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":"PFOS exposure is linked to immune-metabolic disruption in MASLD: integrated population, computational, and experimental evidence.","authors":"Xulei Zuo, Shiyi Tan, Xiaoyu Hou, Cong Zhang, Yuxi Zhang, Juan Zhang","doi":"10.1007/s11030-026-11727-8","DOIUrl":"https://doi.org/10.1007/s11030-026-11727-8","url":null,"abstract":"<p><p>Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), yet the underlying molecular mechanisms remain incompletely characterized. We constructed an integrated analytical framework combining population epidemiology, network toxicology, machine learning, transcriptomic analysis, single-cell mapping, molecular docking, and experimental validation. NHANES data (n = 1,834) were analyzed to assess the association between serum PFOS concentrations and FLI-defined MASLD. Machine-learning analyses using LASSO and SVM-RFE prioritized candidate genes from 874 overlapping PFOS-MASLD-associated genes. Single-cell RNA sequencing resolved cell-type-specific expression patterns, while molecular docking evaluated potential PFOS-protein interactions. A 12-week murine exposure model provided in vivo validation. Epidemiological analysis identified a nonlinear association between serum PFOS and MASLD odds (p < 0.001), with effects evident at background exposure levels (7.76 ng/mL). Convergent machine-learning analyses prioritized five candidate genes: CYP7A1, GRIA3, PHLDA1, SOCS2, and WNT5A. An exploratory five-gene model yielded an apparent AUC of 0.998 (95% CI 0.993-0.998) within the analyzed transcriptomic dataset. Single-cell analysis revealed cell-type specificity, with CYP7A1/PHLDA1 enriched in hepatocytes, SOCS2/WNT5A in hepatic stellate cells, and GRIA3 in T cells. Molecular docking predicted potential PFOS-protein interactions with the five candidate targets, with docking scores ranging from -6.3 to -9.3 kcal/mol. RT-qPCR analysis of PFOS-treated mouse liver showed transcriptional changes consistent with the computational predictions. PFOS-treated mice exhibited hepatic lipid accumulation, elevated liver injury markers, and lipid dysregulation. Together, these findings support an association between PFOS exposure and MASLD-related hepatic dysfunction and propose a hypothesis-generating immune-metabolic framework requiring prospective and direct mechanistic validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dynamic fusion diffusion model for molecular generation.","authors":"Longbin Sun, Xiujuan Lei, Mei Ma","doi":"10.1007/s11030-026-11718-9","DOIUrl":"https://doi.org/10.1007/s11030-026-11718-9","url":null,"abstract":"<p><p>Molecular generation aims to construct valid, diverse, and novel molecular graphs by transforming noise into structured atom and bond representations through reverse diffusion. Because each reverse step relies on accurate denoising, the denoising network must recover both local chemical connectivity and global graph topology across noise levels. We propose DFDM, a dynamic fusion diffusion model for 2D molecular graph generation. DFDM combines a GINE-based spatial branch with a Chebyshev spectral branch and uses signal-to-noise-ratio-guided, layer-specific weights to adapt their contributions during reverse generation. Across three independent seeded generation-and-evaluation runs on QM9 and ZINC250k, DFDM achieved the lowest mean Frechet ChemNet Distance and the highest mean validity without correction among the compared methods. Ablations on both datasets showed that dynamic fusion provided a better overall metric balance than fixed weighting, while QM9 noise-stratified analysis revealed a systematic transition from spectral emphasis at high noise to spatial emphasis near the final denoising stage. DFDM therefore links noise-dependent denoising with molecular graph quality by integrating complementary local and global representations throughout generation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896319","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}