Molecular Diversity最新文献

{"title":"Validated virtual screening models for identifying allosteric inhibitors of ATP-citrate lyase: the role of docking scores and protein-ligand interaction similarity in hit selection.","authors":"Tan Thanh Mai, Nghia Vo-Trong Lai, Thua-Phong Lam, Lam Nguyen-Ngoc Truong, My Ngoc Nguyen, Nghi Van-Tuong Nguyen, Minh-Hoang Phan, Lam-Truong Tuong, Khac-Minh Thai","doi":"10.1007/s11030-026-11519-0","DOIUrl":"https://doi.org/10.1007/s11030-026-11519-0","url":null,"abstract":"<p><p>ATP-citrate lyase (ACLY) is an upstream enzyme involved in fatty acid synthesis, cholesterol metabolism, and histone acetylation. Therefore, selective inhibition of ACLY represents a promising strategy for the treatment of dyslipidemia and various cancers. Recently, the cryo-EM structure of the ACLY complex with the allosteric inhibitor NDI-091143 has been reported, providing an opportunity to discover new potent inhibitors of this emerging target. In this in silico study, we report structure-based models that were rigorously developed and evaluated using reported allosteric inhibitors of ACLY. The pharmacophore model (ROC-AUC = 0.85, GH = 0.78, and EF_1% = 49.18) and the molecular docking model (RMSD_redock = 0.884 Å and ROC-AUC = 0.95) were applied to virtual screening of the ZINC15 library. During hit selection for further evaluation by molecular dynamics simulations, post-docking analysis was performed based on docking scores (ΔG_dock) alone and in combination with the Tanimoto similarity coefficient of protein-ligand interaction fingerprints (Tc_IFP). The combined ΔG_dock and Tc_IFP approach enabled the identification of four out of five selected top hits with binding free energies more favorable than that of the reference compound NDI-091143, supporting their potential as allosteric ACLY inhibitors. These compounds may be subjected to further experimental evaluation to confirm their biological activity. In addition, the workflow developed in the present study may provide a basis for future discovery and optimization of allosteric ACLY inhibitors.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497210","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 anti-liver fibrotic activity study of a chalcone derivative through anti-inflammatory effects and inhibition of JNK/NF-κB signaling pathways.","authors":"Chunwei Lv, Lei Zhang, Chenxu Wang, Tingting Jin, Zhishun Zhang, Yixi Li, Dian He, Quanyi Zhao, Lifang Zheng","doi":"10.1007/s11030-026-11515-4","DOIUrl":"https://doi.org/10.1007/s11030-026-11515-4","url":null,"abstract":"<p><p>Liver fibrosis is a progressive disease caused by chronic inflammation and the activation of hepatic stellate cells (HSCs). This disease manifests as the abnormal proliferation and migration of HSCs, as well as the excessive deposition of the extracellular matrix. Chalcone analogues exhibit various biological activities, including anti-inflammatory, anti-proliferative, and apoptotic modulation properties, making them promising candidates for anti-fibrotic drug development. To enhance anti-fibrotic activities and decrease their side-effects, 31 novel chalcone derivatives were synthesized and evaluated. Among all the compounds, c31 exhibited the strongest anti-inflammatory activity, and its IC₅₀ is 3.05 ± 0.12 µM; and it effectively inhibited the activation and proliferation of HSC-T6 cells. Mechanistic studies revealed that c31 inhibits HSC activation by downregulating the expression levels of inflammatory factors, such as TNF-α, IL-6, and IL-1β, and by interfering with NF-κB and JNK signaling pathways. Additionally, c31 inhibited HSC-T6 proliferation and promoted apoptosis by blocking a G2/M phase cell cycle; and it also significantly inhibited HSC-T6 cell migration. In a rat model of CCl₄-induced liver fibrosis, c31 improved pathological symptoms, decreasing collagen deposition, fibrotic protein expression, and ALT and AST levels. Meanwhile, it also reduced the secretion of inflammatory factors, thereby alleviating CCl₄-induced liver fibrosis. In summary, c31 had significant anti-inflammatory and anti-fibrotic effects in both in vivo and in vitro; this indicates c31 has the potential to be used as a therapeutic candidate for hepatic inflammation and fibrosis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479381","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 putative G-protein-biased µ-opioid agonists via hierarchical virtual screening of ultra-large chemical space.","authors":"Rajkumar R, Tanmaykumar Varma, Prabha Garg","doi":"10.1007/s11030-026-11511-8","DOIUrl":"https://doi.org/10.1007/s11030-026-11511-8","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479416","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":"Cu-catalyzed deaminative thiocyanation of anilines via nitrate reduction.","authors":"Yong-Sheng Zhou, Yan Yang, Jing-Yao Zhou, Li-Jun Xu, Yi-Xie Tan, Xin-Chun Zhang, Liang Wang","doi":"10.1007/s11030-026-11513-6","DOIUrl":"https://doi.org/10.1007/s11030-026-11513-6","url":null,"abstract":"<p><p>An efficient protocol for the synthesis of aryl thiocyanates from anilines and KSCN by merging nitrate reduction with copper-catalysis has been developed. The combination of inexpensive Fe(NO₃)₃·9H₂O and Na₂S₂O₃·5H₂O enabled a safe and green diazotization of anilines. The fleeting diazonium salts reacted with KSCN rapidly to afford the aryl thiocyanates in good to excellent yields using Cu(OTf)₂ as the catalyst. The operational simplicity and safety, good substrate scope and scalability highlight the synthetic significance of this protocol.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479399","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":"2-Quinolone-1,2,3-triazole-benzofuran-N-acylhydrazone hybrids as antiviral and antimicrobial agents: synthesis, in vitro screening and molecular modeling.","authors":"Khadija El Gadali, Meriem Rafya, Az-Eddine El Mansouri, Ahmad Mehdi, Graciela Andrei, Robert Snoeck, Fatiha Benkhalti, Yogesh S Sanghvi, Moha Taourirte, Hassan B Lazrek","doi":"10.1007/s11030-026-11505-6","DOIUrl":"https://doi.org/10.1007/s11030-026-11505-6","url":null,"abstract":"<p><p>To address the growing threat of coinfections and microbial resistance, this study reports the synthesis of a novel multi-pharmacophore scaffold combining 2-quinolone, 1,2,3-triazole, benzofuran and N-acylhydrazone moieties. These hybrids were characterized spectroscopically and assessed for their antiviral, antibacterial and antifungal activities. Most of the tested compounds exhibited interesting efficacy against multiple microbial species. Compound 6a exhibited potent broad-spectrum antimicrobial activity; it completely inhibited E. coli and P. aeruginosa at 0.15 µmol/mL and showed even greater potency against S. aureus (0.08 µmol/mL), outperforming ampicillin and rifampicin. It also inhibited C. glabrata at 0.15 µmol/mL, being 22-fold more potent than fluconazole. Compound 6j displayed dual efficacy against HSV-2 (EC₅₀ = 54.69 µM) and S. aureus (MBC = 0.13 µmol/mL), alongside activity against the fungal strains C. albicans, C. glabrata and C. tropicalis (all with MFCs of 0.25 µmol/mL). Compound 6 m was 4-fold more active than ampicillin against S. aureus (MIC = MBC = 0.07 µmol/mL) and was highly effective against all tested Candida strains (0.14-0.29 µmol/mL). Compound 6p demonstrated pronounced efficacy toward S. aureus and C. albicans at MICs of 0.07 µmol/mL. These active leads (6a, 6j, 6 m and 6p) presented low-to-moderate cytotoxicity on human embryonic lung (HEL) cells, showing morphological changes at MCC values ranging from 20 to 100 µM. Molecular docking revealed high microbial target affinities (binding energies from - 7.1 to - 11.0 kcal/mol), while dynamics simulations confirmed stable 6j binding to S. aureus DNA gyrase and HSV-2 protease. Coupled with favorable ADMET profiles, these hybrids represent promising multitarget antimicrobial candidates.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442325","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 identification of quinoxaline-based 2-pyrazoline hybrids targeting monoamine oxidase A.","authors":"Milendra Kumar Turkar, Gita Chawla","doi":"10.1007/s11030-026-11509-2","DOIUrl":"https://doi.org/10.1007/s11030-026-11509-2","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442348","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":"Synthetic strategies for small molecule compounds for the treatment of Parkinson's disease: targeting α-synuclein.","authors":"Bing Ai, Xin-Yu Zhang, Cai-Yun Hu, Zhen Guo, Cheng-Hua Jin","doi":"10.1007/s11030-026-11510-9","DOIUrl":"https://doi.org/10.1007/s11030-026-11510-9","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442097","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":"Multi-omics investigation of benzo[a]pyrene in gastric cancer: comprehensive network toxicology, machine learning and molecular docking approaches.","authors":"Chunhong Li, Xin Zeng, Yuhua Mao, Shirong Nong","doi":"10.1007/s11030-026-11508-3","DOIUrl":"https://doi.org/10.1007/s11030-026-11508-3","url":null,"abstract":"<p><p>Gastric cancer (GC) risk is shaped by environmental exposures such as benzo[a]pyrene (BaP). Here, we systematically identified BaP-toxicological targets and dissected their contribution to GC development. BaP-related targets were independently predicted with stringent filters from ChEMBL, Similarity Ensemble Approach (SEA) and PharmMapper databases, while GC-related targets were mined from the Comparative Toxicogenomics Database (CTD), GeneCards and OMIM databases. Overlapping targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus GC subtypes, which were subsequently employed 101 machine learning combinations to develop a consensus benzo[a]pyrene-related signature (CBRS) for GC patients. As a result, we identified seven hub toxicological targets: ALB, HSP90AA1, ESR1, INS, TP53, TNF, and EGFR, underscoring their potential central roles in BaP-driven GC pathogenesis. These targets are enriched in the MAPK, Lipid and atherosclerosis, and PI3K-Akt signaling pathway. The BaP-toxicological classifiers and the CBRS prognostic model could provide useful support for risk stratification and inform personalized therapeutic strategies for GC patients. Molecular docking results suggest that BaP exhibits relatively strong binding affinity with these key toxicological targets, potentially implicating their involvement in BaP-induced gastric cancer toxicity. Therefore, this study integrates multi-dimensional omics data with advanced machine learning algorithms to establish a comprehensive analytical framework for the toxicological effects of between BaP and GC, which transcends the limitations of traditional analyses and offers unprecedented insights and evidence chains for elucidating the pathogenesis of GC.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442343","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":"Rational drug design and synthesis of novel bioactive molecules with oxygen heterocycles, including AChE and BChE inhibitory properties and SAR studies.","authors":"Rajarshi Nath, Sumel Ashique, Bhupender Nehra, Ishita Debnath, Suman Ghosh, Pooja A Chawla, Fatimah M Al-Salem, Sabina Yasmin, Md Sadique Hussain, Lakshminarayan Das, Arka Chakraborty, Aganta Chakraborty, Sathvik Belagodu Sridhar, Joy Das, Biplab Debnath, Md Yousuf Ansari","doi":"10.1007/s11030-026-11499-1","DOIUrl":"https://doi.org/10.1007/s11030-026-11499-1","url":null,"abstract":"<p><p>Oxygen-containing heterocycles were reviewed as privileged scaffolds that had driven recent advances in rational drug design and synthetic methodology. The manuscript synthesized literature (2015-2025) on oxadiazoles, coumarins, morpholines, pyrans, furans, benzofurans and chromones and summarized how these scaffolds were engineered to optimize potency, selectivity and CNS drug-like properties. Mechanistic analyses demonstrated that oxygen atoms and carbonyl or ether functionalities consistently mediated key hydrogen-bonding and π-interactions within the catalytic anionic site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), rationalizing observed AChE/BChE SAR and dual-site binding. Representative medicinal chemistry campaigns were highlighted: coumarin and coumarin-hybrid series provided potent dual-site inhibitors; 1,2-oxadiazoles or 1,3,4-oxadiazoles produced sub to low-nanomolar AChE/BChE leads; morpholine-bearing scaffolds afforded favourable BBB permeability and mixed-type inhibition; and pyranone-carbamate hybrids delivered highly BChE-selective inhibitors with promising in vivo cognitive effects. Synthetic strategies (multicomponent reactions, metal-catalysed cyclizations and green/one-pot protocols) were reviewed and correlated with scaffold diversification and improved ADME profiles. The review concluded by identifying gaps limited unified docking/SAR databases and sparse translational safety data and proposed a workflow combining fragment-based design, dual-site targeting and early ADME profiling to accelerate lead optimisation toward clinically relevant cholinesterase modulators. This focused synthesis of structure activity, mechanism and synthetic access was intended to inform future heterocycle-centric programs against neurodegenerative targets.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442104","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":"Current advances in 7-hydroxycoumarin derivatives as potential therapeutic agents for Alzheimer's disease.","authors":"Hiyashree Sharmah, Lokman Ali Ahmed, Durgaprasad Kemisetti, Suresh Kumar, Kumara Swamy Samanthula, Uttam Prasad Panigrahy, Niladry Sekhar Ghosh","doi":"10.1007/s11030-026-11503-8","DOIUrl":"https://doi.org/10.1007/s11030-026-11503-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, remains a major cause of cognitive decline in the aging population. Current pharmacological interventions provide only symptomatic relief, highlighting the urgent need for novel therapeutic strategies capable of modifying disease progression. Coumarins, particularly 7-hydroxycoumarin and its synthetic derivatives, have attracted considerable interest due to their broad pharmacological potential, including cholinesterase inhibition, monoamine oxidase (MAO) inhibition, antioxidant, anti-amyloidogenic and metal-chelating activities. This review presents a comprehensive analysis of synthetic 7-hydroxycoumarin derivatives reported over the past 15 years as potential anti-Alzheimer agents, classifying them according to their actions on key pathological hallmarks of AD, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), MAO-B, β-amyloid (Aβ) aggregation, oxidative stress and neuroinflammation. Structure-activity relationship (SAR) analysis reveals that substitutions at the 7-, 3- and 4-positions of the coumarin scaffold critically influence pharmacological potency and selectivity, with aromatic and alkyl amine substitutions generally enhancing enzyme inhibition and neuroprotective effects. Several derivatives exhibited sub-micromolar to nanomolar inhibitory activity against AChE and MAO-B, along with antioxidant and anti-Aβ aggregation properties, supporting their multifunctional behaviour. Overall, this review highlights the therapeutic promise of 7-hydroxycoumarin derivatives as multitarget-directed ligands (MTDLs) and provides valuable insights for the rational design of new lead compounds for Alzheimer's disease.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353289","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}