Molecular Diversity最新文献_第7页

Effective virtual screening strategy toward JAK3 covalent inhibitors: combining multi‑conformational consensus calculation with covalent docking. JAK3共价抑制剂的有效虚拟筛选策略：多构象一致性计算与共价对接相结合

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-21 DOI: 10.1007/s11030-025-11329-w

Jingyu Zhu, Genhong Qiu, Lei Xu, Yanfei Cai, Yun Chen, Jian Jin

{"title":"Effective virtual screening strategy toward JAK3 covalent inhibitors: combining multi‑conformational consensus calculation with covalent docking.","authors":"Jingyu Zhu, Genhong Qiu, Lei Xu, Yanfei Cai, Yun Chen, Jian Jin","doi":"10.1007/s11030-025-11329-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11329-w","url":null,"abstract":"Accumulating studies have demonstrated that the overactivation of Janus kinase 3 (JAK3) is closely associated with various inflammatory diseases, establishing it as a potential drug target for the treatment of autoimmune and inflammatory disorders. However, the high homology among kinase structures results in poor selectivity for existing JAK3 inhibitors. The approval of the JAK3 covalent inhibitor ritlecitinib has positioned the development of covalent inhibitors as an effective strategy for enhancing JAK3 selectivity. In this study, we developed a hierarchical virtual screening cascade that includes conventional non-covalent approaches and covalent docking steps to identify novel JAK3 covalent inhibitors. First, consensus scoring-based virtual screening was performed by combining the receptor-ligand pharmacophore model with non-covalent molecular docking to pre-screen suitable non-covalently binding conformations and calculate binding energy. Subsequently, covalent molecular docking was conducted to identify molecules that can form covalent bonds with CYS909 in JAK3. This method was validated for its high accuracy while maintaining efficiency. Finally, this virtual screening strategy was employed to screen the SPECS database, resulting in the identification of several compounds with significant potential as covalent JAK3 inhibitors.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938476","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}

引用次数: 0

Correction: Synthesis, anti-tumor evaluation, and mechanistic investigation of 3-indolylpyrazole phenoxyacetamide derivatives against chronic myeloid leukemia cells. 修正：3-吲哚吡唑苯氧乙酰胺衍生物抗慢性髓性白血病细胞的合成、抗肿瘤评价和机制研究。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-21 DOI: 10.1007/s11030-025-11262-y

Mengting Liu, Guiyun Wu, Yue Zhou, Chengpeng Li, Danping Chen, Yan Li, Zhurui Li, Chenchen Li, Zhenchao Wang

引用次数: 0

From structure to strategy: chemometric modeling for the prediction of terminal half-life of pharmaceuticals and its role in future therapeutics. 从结构到策略：预测药物终末半衰期的化学计量学模型及其在未来治疗中的作用。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-21 DOI: 10.1007/s11030-025-11322-3

Pabitra Samanta, Shubha Das, Dipika Mandal, Probir Kumar Ojha

{"title":"From structure to strategy: chemometric modeling for the prediction of terminal half-life of pharmaceuticals and its role in future therapeutics.","authors":"Pabitra Samanta, Shubha Das, Dipika Mandal, Probir Kumar Ojha","doi":"10.1007/s11030-025-11322-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11322-3","url":null,"abstract":"The terminal half-life ( <math><msub><mi>t</mi> <mrow><mn>1</mn> <mo>/</mo> <mn>2</mn></mrow> </msub> </math> ) is a crucial pharmacokinetic parameter for estimating the dose regimen and duration of action of a drug. Previously, few research papers have been published on the pharmacokinetic parameters that correlate with the chemical structure of pharmaceuticals, but these are time-consuming and costly. The main goal of the current study is to generate a quantitative read-across structure-activity relationship (q-RASAR) for terminal half-life estimation of diverse pharmaceuticals. The dataset of 895 pharmaceuticals has been used for 2D descriptor computation and model development. Herein, the combinatorial (q-RASAR) approach of read-across and QSAR has been employed for model generation. Finally, the Partial Least Squares-based q-RASAR model is developed and validated based on the various validation parameters as per the OECD principles. The final q-RASAR model is statistically more significant, reliable, and robust than the corresponding QSAR model based on different statistical parameters (R2 = 0.617, Q2(Loo) = 0.601, error-based predictions = 0.221) and external parameters (Q2F1 & Q2F2 are 0.635). It has been concluded that the presence of the RA function and the presence of 6-membered rings are accountable for the long terminal half-life. Similarly, the presence of the phenol/enol/carboxyl OH group, the presence of positively charged N, solubility, and average molecular weight contribute negatively to the terminal half-life. Additionally, the DrugBank database was screened and predicted the terminal half-life of new and untested pharmaceuticals using the model, which further helped in the prediction of the dosing frequency and accumulation profile of new pharmaceuticals. This study further helps to formulate and optimize safe and eco-friendly pharmaceuticals.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938441","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}

引用次数: 0

Discovery of 7-azaindole-3-acrylamide inhibitors of inflammasomes/IL-1β for the treatment of inflammatory bowel disease. 7-叠氮多尔-3-丙烯酰胺炎症小体抑制剂/IL-1β治疗炎症性肠病的发现

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-20 DOI: 10.1007/s11030-025-11316-1

Yuyun Yan, Xiuxiu Zhang, Ruiwen Wu, Xiangting Liang, Yiming Luo, Jie Yang, Dan Wu, Geng Lin, Ping Sun, Zhongjin Yang, Wenhui Hu

{"title":"Discovery of 7-azaindole-3-acrylamide inhibitors of inflammasomes/IL-1β for the treatment of inflammatory bowel disease.","authors":"Yuyun Yan, Xiuxiu Zhang, Ruiwen Wu, Xiangting Liang, Yiming Luo, Jie Yang, Dan Wu, Geng Lin, Ping Sun, Zhongjin Yang, Wenhui Hu","doi":"10.1007/s11030-025-11316-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11316-1","url":null,"abstract":"Currently, a significant proportion of patients with inflammatory bowel disease (IBD) fail to respond to conventional drug therapies such as immunosuppressants and biologic agents. IL-1 signaling blockade is a promising therapeutic strategy for these unresponsive IBD patients. In this study, we identified a novel anti-NLRP3/ IL-1β inhibitor, the 7-azaindole analogue Y19, which exhibits an IC50 value of 1.26 μM. Mechanistic investigations revealed that it suppresses NLRP3 inflammasome assembly and activation by disrupting critical protein-protein interactions, including NEK7-NLRP3, NLRP3-NLRP3, NLRP3-ASC, and ASC-ASC. Additionally, it also inhibits the AIM2 and NLRC4 inflammasome pathways. In a murine model of colitis, Y19, as a pan-inflammasome inhibitor, demonstrates anti-inflammatory efficacy comparable to that of tofacitinib, a Janus kinase inhibitor commonly prescribed for IBD patients refractory to conventional therapies. This finding highlights the potential of inflammasomes/ IL-1β inhibitors as a promising strategy for the treatment of IBD.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938393","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}

引用次数: 0

Understanding the structural stability and plasticity of VPS34 protein determined by selective/nonselective inhibitors: insights from molecular dynamics simulations. 了解由选择性/非选择性抑制剂决定的VPS34蛋白的结构稳定性和可塑性：来自分子动力学模拟的见解

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-20 DOI: 10.1007/s11030-025-11330-3

Liang Yu, Chu Chen, Qianqian Dong, Fangxin Luo, Jiabing Li, Jiqing Ye

{"title":"Understanding the structural stability and plasticity of VPS34 protein determined by selective/nonselective inhibitors: insights from molecular dynamics simulations.","authors":"Liang Yu, Chu Chen, Qianqian Dong, Fangxin Luo, Jiabing Li, Jiqing Ye","doi":"10.1007/s11030-025-11330-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11330-3","url":null,"abstract":"Vacuolar sorting protein 34 (VPS34), a sole member of class III phosphoinositide 3-kinase (PI3K), regulates critical cellular processes, such as endosomal trafficking and autophagosome biogenesis, making it a promising target for diseases such as cancer and neurodegenerative disorders. However, developing highly selective inhibitors for VPS34 is challenging due to the structural conservation of its ATP-binding site across PI3Ks. In this study, to elucidate the structural dynamics of selective ligand recognition, we performed molecular dynamics (MD) simulations to explore the conformational landscape of VPS34 in both its apo state and in complex with selective/nonselective ligands. MD simulations and trajectory analysis showed that the whole structural stability and rigidity of VPS34 were increased in the presence of selective ligands. Moreover, pocket dynamical analysis demonstrated that the binding pockets were more stable and conserved upon binding to selective ligands. Furthermore, our results indicated that the ligand selectivity was not determined by the ligand's ability to enter the pocket or residue-level interaction energetics. Overall, these results suggested that the ligand selectivity arose from limiting intrinsic dynamics of VPS34 and thereof increasing its rigidity. These findings offer a new mechanistic framework and structural criteria for the rational design and screening of next-generation selective VPS34 inhibitors.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938427","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}

引用次数: 0

Design, synthesis, and biological evaluation of coumarin derivatives against tuberculosis: a pharmacophore-based approach. 香豆素衍生物抗结核的设计、合成和生物学评价：基于药效团的方法。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-20 DOI: 10.1007/s11030-025-11293-5

Suvaiv, Kuldeep Singh, Syed Misbahul Hasan, Rolee Sharma, Kratika Singh, Manu Singh, Firoz Ahmad, Arun Kumar, Syed Mehdi Hasan Zaidi

{"title":"Design, synthesis, and biological evaluation of coumarin derivatives against tuberculosis: a pharmacophore-based approach.","authors":"Suvaiv, Kuldeep Singh, Syed Misbahul Hasan, Rolee Sharma, Kratika Singh, Manu Singh, Firoz Ahmad, Arun Kumar, Syed Mehdi Hasan Zaidi","doi":"10.1007/s11030-025-11293-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11293-5","url":null,"abstract":"Rising cases of drug resistance tuberculosis including multidrug-resistant and extensively drug-resistant emphasize the need for development of drugs with novel mechanism of action. The study aimed to explore novel inhibitors targeting Mycobacterium thymidine monophosphate kinase (Mtb TMPK), a promising but unexplored drug target for tuberculosis treatment. A library of 200 coumarin derivatives was rationally designed and screened against Mtb TMPK, an essential enzyme in nucleotide biosynthesis of mycobacterium tuberculosis. Common feature pharmacophore modeling was performed to identify crucial structural features required for Mtb TMPK inhibition. Molecular docking and ADMET analysis were conducted to prioritize 14 coumarin-piperazine-acetamide derivatives for synthesis. In order to assess the in vitro antitubercular potential of synthesized compounds, the REMA assay was performed. Compound S135, S144, and S146 have shown MIC of 0.06 µg/mL, comparable to the MIC of isoniazid 0.05 µg/mL. All synthesized compounds exhibited promising activity with MIC not exceeding 1 µg/mL, demonstrated the antitubercular potential of designed coumarin analogs. As the design strategy aimed to surpass the issue of whole-cell activity associated with previous Mtb TMPK inhibitors, these results could serve as foundation for this field, supported with green signal from in vitro cytotoxicity study. The findings truly emphasize on Mtb TMPK inhibition assays to fix the mode of action, which could ultimately pave the way for preclinical studies on these derivatives as future perspective.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938313","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}

引用次数: 0

Iron‑catalyzed divergent synthesis of carbazole-based di-/triarylmethanes. 铁催化咔唑基二/三芳基甲烷的发散合成。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-20 DOI: 10.1007/s11030-025-11286-4

Yi-Jun Jiang, Hao-Lan Hu, Yu-Dan Niu, Meng-Yuan Li, Peng Chen

引用次数: 0

Design, synthesis, and mechanism study of novel isoquinoline derivatives containing an oxime moiety as antifungal agents. 新型含肟类抗真菌异喹啉衍生物的设计、合成及机理研究。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-20 DOI: 10.1007/s11030-025-11317-0

Yanxi Jin, Fu Chen, Ying Long, Jianeng Luo, Si Guo, LuYao Wang, Wei Chen

{"title":"Design, synthesis, and mechanism study of novel isoquinoline derivatives containing an oxime moiety as antifungal agents.","authors":"Yanxi Jin, Fu Chen, Ying Long, Jianeng Luo, Si Guo, LuYao Wang, Wei Chen","doi":"10.1007/s11030-025-11317-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11317-0","url":null,"abstract":"A series of novel isoquinoline derivatives 5a-5 s incorporating bioactive amide and oxime ester moieties were rationally designed and synthesized based-on isoquinoline alkaloid scaffolds through pharmacophore splicing strategy. Their structures were verified by 1H NMR, 13C NMR, IR and HRMS. The fungicidal bioassay indicated that most of the target compounds showed good to excellent inhibitory activity against five phytopathogenic fungi in vitro at a concentration of 50 mg/L. Notably, compounds 5 l and 5q exhibited excellent fungicidal activity against S. sclerotiorum with EC50 values reached 8.27 and 8.18 mg/L, respectively, which were comparable to boscalid (8.03 mg/L). 5q exhibited 100% protective and 73.87% curative efficacy against S. sclerotiorum on Brassica napus L. leaves at 100 mg/L. Particularly, compound 5q exhibits potent inhibitory effect against Succinate dehydrogenase (SDH) of S. sclerotiorum with IC50 of 5.05 uΜ. Furthermore, SDH activity assays and molecular docking analyses demonstrated that 5q can interact with SDH in a variety of ways. These results provide substantial insight for the development of novel natural-derived isoquinoline derivatives as potential antifungal agents.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938430","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}

引用次数: 0

Discovery of indole-carbohydrazide hybrids as novel broad-spectrum fungicidal lead compound though membrane-targeting mechanism. 通过膜靶向机制发现吲哚-碳酰肼杂交种作为新型广谱杀真菌先导化合物。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-19 DOI: 10.1007/s11030-025-11326-z

Ying Wu, Li-Hui Shao, Xian-Qun Hu, Yu Long, Yuan-Yuan Wu, Pei-Bu Yu, Ai-Ping Yan, Long-Fei Li, Xiang Zhou, Song Yang

{"title":"Discovery of indole-carbohydrazide hybrids as novel broad-spectrum fungicidal lead compound though membrane-targeting mechanism.","authors":"Ying Wu, Li-Hui Shao, Xian-Qun Hu, Yu Long, Yuan-Yuan Wu, Pei-Bu Yu, Ai-Ping Yan, Long-Fei Li, Xiang Zhou, Song Yang","doi":"10.1007/s11030-025-11326-z","DOIUrl":"10.1007/s11030-025-11326-z","url":null,"abstract":"The escalating prevalence of fungicide resistance has severely diminished the effectiveness of conventional antifungal agents, creating substantial challenges for fungal infection control. To combat this emerging threat, we rationally designed a series of indole-carbohydrazide hybrids, aiming to develop novel membrane-targeting antifungal agents. Of particular note, compound b6 demonstrated optimal antifungal efficacy against Colletotrichum fructicola (C. f., EC50 = 3.39 μg/mL) and Gibberella zeae (G. z., EC50 = 3.49 μg/mL). Comprehensive mechanistic investigations employing multiple approaches-including scanning electron microscopy (SEM), propidium iodide (PI) permeability assays, extracellular conductivity monitoring, and cytoplasmic leakage analysis-collectively revealed that b6 compromised fungal membrane integrity, leading to irreversible cellular damage via increased membrane permeability. Molecular electrostatic potential (MEP) mapping further corroborated the compound's optimal electronic properties for membrane interactions. Comprehensive ADMET analysis demonstrated favorable pharmacokinetic properties, complemented by toxicological evaluations showing exceptional biocompatibility: zebrafish models exhibited a 96-h LC50 > 10 μg/mL, while cytotoxicity assays revealed low toxicity toward various human cell lines. This collective safety profile underscores b6's agricultural applicability. Furthermore, potted plant experiments revealed that compound b6 (200 μg/mL) exhibited protective and curative efficacies of 47.33 and 40.94% against C. f., respectively; these values were comparable or superior to those of the commercial fungicide chlorothalonil. Overall, these findings collectively identified b6 as a promising structural scaffold for developing new antifungal agent alternative, offering significant advantages through its unique membrane-targeting mechanism and synthetic accessibility.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881775","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}

引用次数: 0

Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on transformer model. 基于变压器模型的新型农业真菌琥珀酸脱氢酶抑制剂的设计与优化。

IF 3.8 2区化学

Molecular Diversity Pub Date : 2025-08-19 DOI: 10.1007/s11030-025-11323-2

Yuan Zhang, Jianqi Chai, Ling Li, Wenqian Zhao, Jinwen Ji, Yanru Li, Ziyu Wang, Yuanyuan Chen, Liangyun Zhang, Zhihui Xu, Chunlong Yang, Cong Pian

{"title":"Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on transformer model.","authors":"Yuan Zhang, Jianqi Chai, Ling Li, Wenqian Zhao, Jinwen Ji, Yanru Li, Ziyu Wang, Yuanyuan Chen, Liangyun Zhang, Zhihui Xu, Chunlong Yang, Cong Pian","doi":"10.1007/s11030-025-11323-2","DOIUrl":"10.1007/s11030-025-11323-2","url":null,"abstract":"Succinate dehydrogenase (SDH), also termed complex II or succinate-ubiquinone oxidoreductase, is a crucial biological enzyme in the process of mitochondrial oxidative phosphorylation. Succinate dehydrogenase inhibitors (SDHIs) are a promising class of fungicides targeting the energy production pathway of pathogenic fungi. However, overuse has resulted in the emergence of resistance, underscoring the need for novel and effective SDHIs. This study utilized the Transformer model to generate a customized virtual library of potential SDHIs. These candidates were then meticulously screened based on expert knowledge and synthetic feasibility, ultimately yielding several pyrazole carboxamide derivatives as the promising leads. Subsequent synthesis, antifungal activity assessment, and structural optimization further refined these leads into potent SDHI candidates. This work represents the first application of a generative model to SDHI design, establishing a robust workflow encompassing virtual library generation, screening, activity evaluation, and structure optimization. This study paves the way for the rational design of future SDHIs, not only against fungi, but potentially other agricultural pathogens as well.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870790","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}

引用次数: 0