Molecular Diversity最新文献

{"title":"Reductive coupling of 2,2'-dinitrobiphenyls into benzo[c]cinnolines with NaHS.","authors":"Pingbing Yu, Zhaoyue Wen, Chun Wang, Jianlian Wu, Tie-Gen Chen, Wei Chen","doi":"10.1007/s11030-024-11087-1","DOIUrl":"https://doi.org/10.1007/s11030-024-11087-1","url":null,"abstract":"<p><p>An efficient and selective method for the reduction of 2,2'-dinitrobiphenyls with NaHS to prepare benzo[c]cinnoline and benzo[c]indole N-oxide was developed. This reductive coupling protocol proceeded as quick as 20 min, and gave moderate to good yields under ambient conditions. It was straightforward and easily scalable to produce various of benzo[c]cinnoline derivatives with diverse substitution patterns.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187617","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":"Evaluation of selected indigenous spices- and herbs-derived small molecules as potential inhibitors of SREBP and its implications for breast cancer using MD simulations and MMPBSA calculations.","authors":"Urvashi Tiwari, Salman Akhtar, Snober S Mir, Mohammad Kalim Ahmad Khan","doi":"10.1007/s11030-025-11122-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11122-9","url":null,"abstract":"<p><p>In this study, we conducted an extensive analysis of 252 bioactive compounds derived from native spices and herbs for their potential anti-breast cancer activity against sterol regulatory element-binding protein (SREBP), using in silico techniques. To evaluate the oral bioavailability, overall pharmacokinetics, and safety profiles of these compounds, we employed Lipinski's rule of five and ADME descriptors, which depicted 66 lead molecules. These molecules were then docked with the SREBP using molecular docking tools, which revealed that diosgenin and smilagenin were the most promising hits compared to the reference inhibitor betulin, with average binding affinities of - 7.42 and - 7.37 kcal/mol and - 6.27 kcal/mol, respectively. To further assess the stability of these complexes along with betulin, we conducted molecular dynamics simulations over a 100 ns simulation period. We employed various parameters, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, free energy of solvation, and radius of gyration, followed by principal component analysis. Furthermore, we evaluated the toxicity of the selected compounds against various anticancer cell lines, as well as their metabolic activity related to CYP450 metabolism and biological activity spectrum. Based on these results, both molecules exhibited promising drug candidate potential and could be utilized for further experimental analysis to elucidate their anticancer potential.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078355","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 novel A_2AR antagonist via 3D-QSAR pharmacophore modeling: neuroprotective effects in 6-OHDA-induced SH-SY5Y cells and haloperidol-induced Parkinsonism in C57 bl/6 mice.","authors":"Ankit Singh, Amresh Prakash, Jyoti Mishra, Pratibha Mehta Luthra","doi":"10.1007/s11030-025-11120-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11120-x","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder which is caused by abrupt degeneration of dopaminergic neuronal cells in the substantia nigra pars compacta (SNPc) area of the midbrain. Adenosine A_2A receptors have become promising therapeutic targets for PD; however, many A_2A receptor antagonists face challenges, such as limited accessibility or failure in clinical trials due to poor selectivity and bioavailability. To identify novel A_2A receptor antagonists, a 3D-QSAR-pharmacophore modeling approach was employed, involving virtual screening of ZINC, NCI, and MayBridge databases. The virtual hits were filtered via ADMET criteria to select compounds with favorable bioavailability and solubility profiles. From the MayBridge database, a potent monocyclic A_2A receptor antagonist, AW00032 (N-(furan-2-ylmethyl)-5-methylthiazole-4-yl) thiophene-2-sulfonamide, was identified. AW00032 possessed key pharmacophoric features: two lipophilic hydrogen bond acceptors, one hydrophobic aliphatic/aromatic group, and one aromatic ring. Docking analysis revealed AW00032 had a strong binding affinity for A_2A receptors (1.23 nM, ∆G - 10.49 kcal/mol), and its ADMET profile indicated good bioavailability. In 6-OHDA induced SH-SY5Y cells, AW00032 increased dopamine levels and tyrosine hydroxylase (TH) expression, demonstrating its potential as an A_2A receptor antagonist. AW00032, discovered through 3D-QSAR pharmacophore modeling, also reduced reactive oxygen species (ROS) levels and showed depletion in mitochondrial dysfunction in 6-OHDA-induced SH-SY5Y cells. It exhibited A_2A receptor antagonist activity comparable to the standard antagonist ZM241385, partially restoring dopamine and TH levels. Furthermore, AW00032 improved behavioral symptoms in haloperidol-induced C-57 bl/6 mice.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078427","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":"Thiazolidinedione derivatives: emerging role in cancer therapy.","authors":"Ganesh Latambale, Kapil Juvale","doi":"10.1007/s11030-024-11093-3","DOIUrl":"https://doi.org/10.1007/s11030-024-11093-3","url":null,"abstract":"<p><p>Cancer remains the leading cause of death worldwide, with the Globocan 2022 study reporting an estimated 9.7 million cancer deaths. Without the selectivity built for tumour cells, chemotherapeutic agents could be toxic to non-cancerous cells. Administration of such non-selective cytotoxic compounds causes severe side effects and could lead to death. Improved cancer treatments are required to overcome the limitations of the current cancer treatment. The potential of thiazolidinedione derivatives as anticancer drugs has recently drawn attention, despite their primary use as insulin sensitizers in the treatment of type 2 diabetes. The ability of thiazolidinedione derivatives to alter important molecular pathways implicated in carcinogenesis, such as cell proliferation, apoptosis, angiogenesis, Raf kinase, EGFR and HER-2 kinases, HDAC, COX-2 enzyme and metastasis, is highlighted in this review, which examines the growing relevance of these compounds in cancer treatment. Thiazolidinediones have anti-inflammatory, antioxidant, and antiproliferative properties in a variety of cancer types, including breast, colon, and prostate cancers, via activating the peroxisome proliferator-activated gamma receptor (PPARγ). In addition to examining the safety profile and difficulties in clinical translation, the paper looks at preclinical and clinical research that points to these medicines potential to improve the effectiveness of immunotherapy and chemotherapy. This review highlights the encouraging therapeutic possibilities and structure-activity relationship insight of TZDs for their anticancer activity and highlights the molecular level facets of the 'glitazone' pharmacophore for its anticancer activity.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078363","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-based screening and molecular simulations for discovering novel PARP-1 inhibitors targeting DNA repair mechanisms for breast cancer therapy.","authors":"Muhammad Shahab, Muhammad Waqas, Aamir Fahira, Bharat Prasad Sharma, Haoke Zhang, Guojun Zheng, Zunnan Huang","doi":"10.1007/s11030-025-11119-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11119-4","url":null,"abstract":"<p><p>Cancer remains one of the leading causes of death worldwide, with the rising incidence of breast cancer being a significant public health concern. Poly (ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising therapeutic target for breast cancer treatment due to its crucial role in DNA repair. This study aimed to discover novel, targeted, and non-toxic PARP-1 inhibitors using an integrated approach that combines machine learning-based screening, molecular docking simulations, and quantum mechanical calculations. We trained a widely used machine learning models, Random Forest, using bioactivity data from known PARP-1 inhibitors. After evaluating the performance, it was used to screen an FDA-approved drug library, successfully identifying Atazanavir, Brexpiprazole, Raltegravir, and Nisoldipine as potential PARP-1 inhibitors. These compounds were further validated through molecular docking and all-atom molecular dynamics simulations, highlighting their potential for breast cancer therapy. The binding free energies indicated that Atazanavir at - 41.86 kJ/mol and Brexpiprazole at - 45.44 kJ/mol exhibited superior binding affinity compared to the control drug at - 30.42 kJ/mol, highlighting their promise as candidates for breast cancer therapy. Subsequent optimized geometries and electron density mappings of the two molecular structures revealed a Gibbs free energy of - 2334.610 Ha for the first molecule and - 1682.278316 Ha for the second, confirming enhanced stability compared to the standard drug. This study not only highlights the efficacy of machine learning in drug discovery but also underscores the importance of quantum mechanics in validating molecular stability, setting a robust foundation for future pharmacological explorations. Additionally, this approach could revolutionize the drug repurposing process by significantly reducing the time and cost associated with traditional drug development methods. Our results establish a promising basis for subsequent research aimed at optimizing these PARP-1 inhibitors for clinical use, potentially offering more effective treatment options for breast cancer patients.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078359","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":"PPARγ modulator predictor (PGMP_v1): chemical space exploration and computational insights for enhanced type 2 diabetes mellitus management.","authors":"Sk Abdul Amin, Lucia Sessa, Shovanlal Gayen, Stefano Piotto","doi":"10.1007/s11030-025-11118-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11118-5","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in adipocyte differentiation and enhances insulin sensitivity. In contemporary drug discovery, in silico design strategies offer significant advantages by revealing essential structural insights for lead optimization. The study is guided by two main objectives: (i) a ligand-based approach to explore the chemical space of PPARγ modulators followed by molecular docking ensembles (MDEs) to investigate ligand-binding interactions, (ii) the development of a supervised ML model for a large dataset of compounds targeting PPARγ. Additionally, the combination of chemical space networks with ML models enables the rapid screening and prediction of PPARγ modulators. These modeling analyses will assist medicinal chemists in designing more potent PPARγ modulators. To further enhance accessibility for the scientific community, we developed an online tool, \"PGMP_v1,\" aimed at prospective screening for PPARγ modulators. The tool \"PGMP_v1\" is available at the provided link https://github.com/Amincheminfom/PGMP_v1 . The integration of these computational methods has uncovered crucial structural motifs that are essential for PPARγ activity, advancing the development of more effective modulators in the future.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073424","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 natural products as influenza neuraminidase inhibitors: in silico screening, in vitro validation, and molecular dynamic simulation studies.","authors":"Binglin Huang, Bijuan Lin, Hansen Zheng, Bin Zheng, Xin Xue, Maobai Liu","doi":"10.1007/s11030-025-11115-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11115-8","url":null,"abstract":"<p><p>Influenza is a highly contagious respiratory illness that imposes a significant global burden. Antiviral neuraminidase inhibitors (NAIs) such as oseltamivir (OC) have been proven essential, but the emergence of resistant viral strains necessitates the development of novel therapies. This study explored the potential of natural products as alternative NAIs. We used virtual screening against the Chinese Ethnic Characteristic Drug Database, followed by Quantum Mechanics/Molecular Mechanics Generalized Born Surface Area (QM/MM-GBSA) rescoring with ligands treated as QM region. Compounds preserved from docking-based virtual screening were reranked based on QM/MM-GBSA scores, and the top 15 compounds with binding free energy lower than that of native inhibitor OC were selected for NA inhibitory assay. Among the tested compounds, compounds T6S0444 (Salvianolic acid A) demonstrated significant inhibitory activity against both wild-type and H274Y-mutated influenza NAs, suggesting their potential as novel anti-influenza agents. Specifically, compound T6S0444 exhibited greater inhibitory activity against N2-H274Y than the wild-type N2, with IC₅₀ values of 5.3 ± 0.4 µM and 12.8 ± 1.2 µM, respectively. This distinctive selectivity for mutant viral strains is not observed in current antiviral drugs for influenza. Furthermore, these compounds demonstrated low cytotoxicity, indicating their potential as safe anti-influenza agents. In summary, we have identified a promise NA inhibitor, T6S0444, a potential therapeutic for the treatment of oseltamivir-resistant influenza.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063081","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":"Explanatory review on DDR inhibitors: their biological activity, synthetic route, and structure-activity relationship.","authors":"Sindhuja Sengupta, Lalmohan Maji, Pronoy Kanti Das, Ghanshyam Teli, Mrinmoy Nag, Nirmalya Khan, Mridul Haque, Gurubasavaraja Swamy Purawarga Matada","doi":"10.1007/s11030-024-11091-5","DOIUrl":"https://doi.org/10.1007/s11030-024-11091-5","url":null,"abstract":"<p><p>Discoidin domain receptors (DDR) are categorized under tyrosine kinase receptors (RTKs) and play a crucial role in various etiological conditions such as cancer, fibrosis, atherosclerosis, osteoarthritis, and inflammatory diseases. The structural domain rearrangement of DDR1 and DDR2 involved six domains of interest namely N-terminal DS, DS-like, intracellular juxtamembrane, transmembrane juxtamembrane, extracellular juxtamembrane intracellular kinase domain, and the tail portion contains small C-tail linkage. DDR has not been explored to a wide extent to be declared as a prime target for any particular pathological condition. Very few scientific data are available so there is a need to study the receptors and their inhibitors. Still, there did not exist FDA-approved small molecules targeting DDR1 and DDR2 receptors so there is an urgent need to develop potent small molecules. Further, the structural features and ligand specificities encourage the researchers to be fascinated about the DDR and explore them for the mentioned biological conditions. Therefore, in the last few years, researchers have been involved in investigating the potent DDR inhibitors. The current review provides an outlook on the anatomy and physiology of DDR, focusing on the structural features of DDR receptors and the mechanism of signaling pathways. We have also compiled the evolutionary development status of DDR inhibitors according to their chemical classes, biological activity, selectivity, and structure-activity relationship. From biological activity analysis, it was revealed that compounds 64a (selectivity: DDR1) and 103a (selectivity: DDR2) were the most potent candidates with excellent activity with IC₅₀ values of 4.67 and 3.2 nM, respectively.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063084","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":"Pharmacoinformatics-based screening and construction of a neutralizing anti-SARS-CoV-2 camelidae nanobody drug conjugate.","authors":"Elora Kalita, Mamta Panda, Sarthak Dhar, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1007/s11030-024-11086-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11086-2","url":null,"abstract":"<p><p>Nanobodies or variable antigen-binding domains (V_HH) derived from heavy chain-only antibodies (HcAb) occurring in the Camelidae family offer certain superior physicochemical characteristics like enhanced stability, solubility, and low immunogenicity compared to conventional antibodies. Their efficient antigen-binding capabilities make them a preferred choice for next-generation small biologics. In the present work, we design an anti-SARS-CoV-2 bi-paratopic nanobody drug conjugate by screening a nanobody database. SAbDab-nano database was screened based on the physicochemical properties and SARS-CoV-2 binding affinity of the documented nanobodies. Molecular docking, computational modeling, in silico site-directed mutagenesis, and MD simulations were performed to construct an effective nanobody bi-paratope. The construct's physicochemical properties were assessed, and its structural integrity was validated through model energy refinement and quality assessment. The triple-mutant (N78Q K116N T123F) nanobody, based on the bioinformatics analysis, exhibited enhanced binding efficiency against its targets: SARS CoV-2 WT RB (- 353.3), NRP1 (- 376.5) and Omicron RBD (- 380.8), compared to the WT nanobody (SARS CoV-2 WT RBD = - 337.5, NRP1 = - 361.5, Omicron RBD = - 359.5). In silico evaluation also predicted that the construct would demonstrate efficient solubility, high thermostability (Tm 67.4 °C), low molecular weight of 29.36 KDa, and non-toxic, non-allergenic properties. Anti-SARS-CoV-2 neutralizing nanobody-based therapeutics, as demonstrated through this computational work, represents a promising alternative to traditional COVID-19 prophylaxis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051163","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":"Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure-activity relationship analysis.","authors":"Neethu Mariam Thomas, Majed Alharbi, Venkanna Muripiti, Janardhan Banothu","doi":"10.1007/s11030-024-11092-4","DOIUrl":"10.1007/s11030-024-11092-4","url":null,"abstract":"<p><p>Quinoline is a highly privileged scaffold with significant pharmacological potential. Introducing a carbonyl group into the quinoline ring generates a quinolone ring, which exhibits promising biological properties. Incorporating a carboxamide linkage at different positions within the quinoline and quinolone frameworks has proven an effective strategy for enhancing pharmacological properties, particularly anticancer potency. Consequently, various scientific communities have explored quinoline and quinolone carboxamides for their anticancer activities, introducing modifications at key positions. This review article aims to compile the anticancer activity of various quinoline and quinolone carboxamide derivatives, accompanied by a detailed structure-activity relationship (SAR) analysis. It also categorizes the data into activities of isolated/fused quinoline and quinolone carboxamide derivatives, which were further subclassified based on the mechanisms of anticancer action. Among the numerous derivatives studied, compounds 8, 19, 31, 34, 40, 68, 108, 116, and 132 have emerged as the most potent anticancer agents, making them strong candidates for further drug design and development. The mechanisms underlying the anticancer activity of these potent compounds have been identified as inhibitors of topoisomerase (8, 19, 31, and 34), protein kinase (40, 108, and 116), human dihydroorotate dehydrogenase (68), and as a cannabinoid receptor 2 agonist (132). We anticipate this review will be valuable to researchers engaged in the structural design and development of quinoline and quinolone carboxamide-based anticancer drugs with high efficacy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051248","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}