Molecular Diversity最新文献

{"title":"Correction: Computational approach for the evaluation of sesquiterpene lactone as a modulator of cannabinoid receptor type 2 for neurodegenerative disease prophylactics.","authors":"Ram Lal Swagat Shrestha, Ashika Tamang, Sujan Dhital, Nirmal Parajuli, Manila Poudel, Safal Adhikari, M C Shiva, Aakar Shrestha, Timila Shrestha, Samjhana Bharati, Binita Maharjan, Bishnu P Marasini, Jhashanath Adhikari Subin","doi":"10.1007/s11030-025-11218-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11218-2","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075295","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 and synthesis of stilbene analogs based on resveratrol as NF-κB inhibitors for the treatment of breast cancer.","authors":"Shaojuan Fu, Yu Zhang, Yuanli Yang, Xing Lu, Yanni Wang, Lingling Lei, Junjie Lan, Huan He, Silong Zhang, Weidong Pan","doi":"10.1007/s11030-025-11212-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11212-8","url":null,"abstract":"<p><p>NF-κB is a critical signaling molecule connecting inflammation and tumors, involved in numerous cellular processes, including inflammation, cell transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis by regulating immune, growth, and inflammatory gene expression. Inhibition of the NF-κB signaling pathway in tumor cells can effectively reduce inflammation levels, potentially providing antitumor benefits. Resveratrol, a natural polyphenolic compound known for its anti-inflammatory properties, has been shown both anti-inflammatory and anticancer effects in breast cancer cells through the inhibition of NF-κB signaling. Based on the stilbene structure of Resveratrol, we designed and synthesized a series of novel analogs. Preliminary screening indicated that compound 8a exhibited not only anti-inflammatory and antiproliferative effects but also suppressant on the expression of inflammatory factors in MCF-7 breast cancer cells. To gain a deeper understanding of its mechanism of action, we further investigated the inhibitory effect of compound 8a on the NF-κB signaling pathway. The study found that compound 8a can significantly reduce the expression levels of key proteins p65 and IκBα in the classical NF-κB signaling pathway and effectively prevent the entry of p65 protein into the nucleus, thereby exhibiting potent anti-inflammatory effects and potential anti-breast cancer activity. Molecular docking analysis results show that compound 8a interacts with the NF-κB p65 protein through two crucial hydrogen bonds, and this binding affinity is even superior to that of the known Resveratrol. In summary, compound 8a could be a promising drug lead, as a NF-κB inhibitor for breast cancer treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085630","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 and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide‑1 receptor agonists.","authors":"Wanting Zhao, Yuqian Yin, Zhuo Shi, Ke Yang, Xinglin Li, Yushe Yang, Tongfei Jing, Zhenghui Kang","doi":"10.1007/s11030-025-11213-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11213-7","url":null,"abstract":"<p><p>Several glucagon-like peptide-1 receptor (GLP-1R) agonists have been recognized as effective therapeutic strategies for T2DM and obesity. Our efforts focused on modifying the pyridine fragment and the region near the benzo[d]imidazole moiety of danuglipron to reduce the inhibitory activity on the hERG channel while preserving its ability to activate GLP-1R, leading to the synthesis of 21 novel derivatives. An optimized indolecarboxylic acid derivative, YK-11 (EC₅₀ = 7.5 nM), showed promising ability in activating GLP-1R, with acceptable inhibition of the hERG ion channel (IC₅₀ = 34.3 μM). Furthermore, the docking analysis of YK-11 revealed that indolecarboxylic acid derivatives extended into the binding pocket of the GLP-1R protein in a similar manner to danuglipron, and the carboxyl group, methyl ester moiety, cyano group and cyclobutyl ether moiety of YKF-11 created four hydrogen bonds with Lys197, Gln221 and Arg299, respectively. This study provided alternative approach for the future development of GLP-1R agonists.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959514","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-Amino-1,4-naphthoquinone as a key precursor for naphthoquinone-fused N-heterocycles: synthetic approaches and mechanistic perspectives.","authors":"Ujjain Chaurasia, Tasneem Parvin","doi":"10.1007/s11030-025-11201-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11201-x","url":null,"abstract":"<p><p>2-Amino-1,4-naphthoquinone has gained significant attention as a key precursor for constructing naphthoquinone-fused N-heterocycles, a class of compounds with broad applications in medicinal chemistry, materials science, and organic synthesis. Its unique structure, characterized by a reactive C-3 position and an amino group, facilitates a wide range of reactions and synthetic strategies. This review provides a comprehensive overview of recent advancements (2012-2024) in utilizing 2-amino-1,4-naphthoquinone for the development of N-heterocyclic frameworks integrating synthetic approaches with mechanistic insights. It is organized based on the type of heterocyclic rings formed, leveraging the C,N-binucleophilic properties of 2-amino-1,4-naphthoquinone.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967689","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":"Identifying potent inhibitors for Mycobacterium tuberculosis MabA (FabG1).","authors":"Debashis Panda, Jitendra Maharana, Arjun Sharma, Sachin B Wadavrao, Abhishek Chowdhury, Monjur Ahmed Laskar, Mahendra K Modi, Manabendra D Choudhury","doi":"10.1007/s11030-025-11205-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11205-7","url":null,"abstract":"<p><p>The surge in drug-resistant Mycobacterium tuberculosis (Mtb) strains poses formidable challenges for tuberculosis treatment, emphasizing the pressing need to explore novel therapeutic agents. Mycolic acids, essential for bacterial cell wall formation, are synthesized by two fatty acid synthase (FAS) systems: FAS-I and FAS-II. MabA, an enzyme in the FAS-II system, is vital in the second step of fatty acid biosynthesis and is responsible for the elongation of mycolic acids. In this study, we screened 1,792,771 compounds from seven different databases to screen prospective inhibitors of MabA, an emerging therapeutic target for Mtb. Using a combination of molecular docking, all-atom molecular dynamics simulations, and binding free energy calculations, we identified 48 novel lead compounds from five distinct classes that exhibit significant binding activity against MabA. Of these, 47 compounds demonstrated significantly higher MM/PBSA binding free energy than the only reported MabA inhibitor, compound 29. Altogether, our findings mark a significant advancement towards the rational design of novel therapeutics aimed at combating mycobacterial infections and overcoming drug resistance.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955126","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":"From pharmacophore predictions to pharmaceutical possibilities: an integrated approach to screen M₃ selective muscarinic receptor antagonist.","authors":"Sirat K Gill, Swati Kumari, Bichitra K Biswal, Badri N Acharya","doi":"10.1007/s11030-025-11208-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11208-4","url":null,"abstract":"<p><p>Muscarinic Acetylcholine Receptors (mAChR) are located in the central nervous system, peripheral nervous system, nerve synapses, and autonomic ganglia. They are coupled with G-proteins that regulate a range of functions like motor control, cardiac rhythm, smooth muscle contraction-relaxation, and glandular secretions. Muscarinic receptors have five subtypes that span from M₁ to M₅. Among them, M₃ mAChR has gained significant attention as per their involvement in irritable bowel syndrome, over active bladder, and chronic obstructive pulmonary disease. To identify M₃ selective antimuscarinic drugs using virtual screening, a five-feature three-dimensional quantitative structure-activity relationship pharmacophore model was generated with 0.962 correlation coefficient and 0.728 root mean square deviation. It was trained such that it passed Fischer's Randomization test at a 99% confidence level. The screened active molecules were calculated for pharmacokinetic properties to define drug-likeliness, and flexibly docked on receptors with a defined binding pocket to reach M₃ selective mAChR antagonists. For the leading candidates, calculating Molecular-Mechanics-Generalized-Born Surface Area binding free energy gave the optimal conformer for molecular dynamics studies. The generated frames showed molecule 45255447 (PubChemID) to be most stable at M₃ mAChR binding pocket and can be put forward for therapeutic potential through wet lab analysis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958167","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":"Enhancing PI3Kγ inhibitor discovery: a machine learning-based virtual screening approach integrating pharmacophores, docking, and molecular descriptors.","authors":"Lei Jia, Lei Xu, Yanfei Cai, Yun Chen, Jian Jin, Li Yu, Jingyu Zhu","doi":"10.1007/s11030-025-11216-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11216-4","url":null,"abstract":"<p><p>PI3Kγ is a lipid kinase that is expressed primarily in leukocytes and plays a significant role in tumors, inflammation, and autoimmune diseases. Consequently, considerable attention has been given to the development of pharmacological inhibitors of PI3Kγ. Recently, machine learning-based virtual screening approaches have been increasingly applied in new drug discovery research, potentially providing innovative strategies for the development of PI3Kγ inhibitors. Thus, in this study, we developed a naïve Bayesian classification (NBC) model that integrates molecular descriptors, molecular fingerprints, molecular docking, and pharmacophore models for virtual screening of the PI3Kγ protein. The validation results indicated that the optimal model demonstrated significant potential for differentiating between active and inactive compounds, as well as a reliable ability to identify true PI3Kγ inhibitors with defined biological activity. Additionally, the optimal NBC model provided favorable and unfavorable fragments for PI3Kγ inhibitors, which will help guide the design and discovery of novel PI3Kγ inhibitors. Finally, the optimal NBC model was employed to perform virtual screening on the ChEMBL database, resulting in the identification of several compounds with high potential as PI3Kγ inhibitors. We anticipate that the developed machine learning-based virtual screening approach will offer valuable insights and guidance for the development of novel PI3Kγ inhibitors.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958003","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 of WBmDapE and deciphering of potent anti-filarial inhibitors: a state-of-art computational approach.","authors":"Poopandi Saritha, Nagarajan Hemavathy, Subramaniyan Sneha, Dhamodharan Prabhu, Vetrivel Umashankar, Jeyaraman Jeyakanthan","doi":"10.1007/s11030-025-11207-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11207-5","url":null,"abstract":"<p><p>Lymphatic filariasis (LF) stands as a debilitating tropical ailment, impacting a considerable global populace. Existing drug therapies for LF exhibit limited effectiveness across all parasite stages, thereby accentuating the imperative for novel anti-filarial medications characterized by enhanced prognostic attributes and minimized adverse reactions. A promising avenue involves targeting the microbial enzyme WBmDapE, pivotal in worm survival and intricately linked to the lysine biosynthetic pathway and peptidoglycan cell wall construction. This investigation employs in silico methodologies encompassing molecular docking, Molecular Dynamics Simulation (MDS), conformational analysis, Shape-Based Virtual Screening (SBVS), ADMETox, MMGBSA, and Density Functional Theory (DFT) calculations to discern potential inhibitors of WBmDapE. Through discerning the conformational shifts of the WBmDapE-bound substrate and product, key amino acids implicated in substrate binding (Arg182 and Asp248) are unveiled. While the apo and substrate-bound structures exhibit an open conformation, the product-bound structure displays marked conformational alterations, including shifts within the catalytic domain and the cofactor in the dimerization domain, suggestive of an active and closed conformation. From the prism of shape-based virtual screening, two preeminent compounds (ZINC42784280 and ZINC84308049) have surfaced as potential hits. These compounds evince heightened binding affinity, optimal binding free energy, pivotal hydrogen bond interactions, and akin attributes to the product-bound complex. Subsequently, these compounds emerge as prospective candidates for filariasis treatment. In summation, our study furnishes invaluable insights into the fabrication of innovative WBmDapE inhibitors, potentially serving as anti-filarial agents. Rigorous experimental substantiation and fine-tuning of these compounds are requisite for prospective therapeutic interventions against LF.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962951","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":"sCentInDB: a database of essential oil chemical profiles of Indian medicinal plants.","authors":"Shanmuga Priya Baskaran, Geetha Ranganathan, Ajaya Kumar Sahoo, Kishan Kumar, Jayalakshmi Amaresan, Kundhanathan Ramesh, R P Vivek-Ananth, Areejit Samal","doi":"10.1007/s11030-025-11215-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11215-5","url":null,"abstract":"<p><p>Essential oils are complex mixtures of volatile compounds produced by aromatic plants and widely used in personal care, food flavoring, and pharmaceutical industry due to their odor and therapeutic properties. As a high-value and low-volume organic product, optimizing plant yield and modifying composition by leveraging knowledge on chemical profiles of essential oils can lead to enhanced bioproducts. Additionally, overharvesting of wild medicinal plants, especially in India, threatens biodiversity. Essential oil profiles of such plants can help regulate their exploitation. Here, we present sCentInDB, a manually curated FAIR-compliant DataBase of Essential oil Chemical profiles of Medicinal plants of India, compiled from published literature. sCentInDB contains data on 554 Indian medicinal plants at the plant part level, encompassing 2170 essential oil profiles, 3420 chemicals, 471 plant-part-therapeutic use associations, 120 plant-part-odor associations, and 218 plant-part-color associations. sCentInDB also compiles metadata such as sample location, isolation, and analysis methods. Subsequently, an extensive analysis of the chemical space in sCentInDB was performed. By constructing a chemical similarity network, terpenoids were found to be distributed across the network, indicating greater structural diversity. Moreover, a comparison of the scaffold diversity of chemicals in sCentInDB was performed against three other aroma libraries using cyclic system retrieval curves. Altogether, sCentInDB will serve as a valuable resource for researchers working on plant volatiles and employing genetic engineering to enhance oil yield and composition. Further, sCentInDB will aid in the establishment of quality standards for essential oils and provide vital insights for therapeutic and perfumery applications. sCentInDB is accessible at https://cb.imsc.res.in/scentindb/ .</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952371","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":"Unraveling potent Glycyrrhiza glabra flavonoids as AKT1 inhibitors using network pharmacology and machine learning-assisted QSAR.","authors":"Desu Gayathri Niharika, Punam Salaria, Amarendar Reddy M","doi":"10.1007/s11030-025-11210-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11210-w","url":null,"abstract":"<p><p>Glycyrrhiza glabra (G. glabra) phytocompounds have been reported to interact with neurological targets, including those implicated in epilepsy, and may modulate epilepsy-related targets. While substantial evidence supports their potential antiepileptic effects, the underlying molecular mechanisms remain unclear. This study aims to elucidate the molecular mechanism of G. glabra phytocompounds by integrating network pharmacology and machine learning (ML)-based quantitative structure-activity relationship (QSAR) techniques. Network pharmacology analysis identified AKT1 as a key epilepsy-related target, and four ML-based 2D-QSAR models were developed using AKT1 inhibitors. The developed models underwent comprehensive validation, including internal and external validation, Y-randomization, statistical analysis, and applicability domain assessment to ensure robustness and reliability. Among them, the Multilayer Perceptron (MLP) model excelled as the most robust and demonstrated superior predictive ability with a correlation coefficient r²_training = 0.95, r²_test = 0.84, and cross-validation coefficient q² = 0.72. The MLP model accurately predicted pIC₅₀ values of phytoflavonoids, leading to the identification of 19 active molecules through the activity atlas model. ADME and drug-likeliness screening narrowed the selection to eleven promising compounds for further docking analysis. Molecular docking highlighted glabranin and 3'-hydroxy-4'-O-methylglabridin as top lead compounds with a binding energy of - 5.75 and - 5.37 kcal/mol, respectively. Additionally, 400 ns molecular dynamics simulation confirmed the structural and conformational stability of the glabranin-AKT1 complex, further reinforced by Principal Component Analysis, free energy landscapes, and Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area. Collectively, these findings underscore the potential of G. glabra phytocompounds as promising antiepileptic candidates, paving the way for future advancements in this field.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958301","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}