Molecular Diversity最新文献

{"title":"A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study","authors":"Madhumitha Suresh, Kadambari Vijay Sai, Kartik Mitra, Radhika Ravindran, Mukesh Doble","doi":"10.1007/s11030-024-10985-8","DOIUrl":"https://doi.org/10.1007/s11030-024-10985-8","url":null,"abstract":"<p>The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, <i>Acacia nilotica</i>, as a model system. The protein–protein interaction network revealed 17 key pathways in <i>M. tuberculosis</i> encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of <i>A. nilotica</i> were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against <i>M. smegmatis</i>) with specific inhibition of purified <i>M.tb</i> FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260478","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":"Metal complexes containing vitamin B6-based scaffold as potential DNA/BSA-binding agents inducing apoptosis in hepatocarcinoma (HepG2) cells","authors":"Almuhrah A. N. Alroba, Elham Shafik Aazam, Mehvash Zaki","doi":"10.1007/s11030-024-10986-7","DOIUrl":"https://doi.org/10.1007/s11030-024-10986-7","url":null,"abstract":"<p>A ligand (<b>HL</b>) was synthesized from the pyridoxal hydrochloride (vitamin B6 form) and 1-(2-Aminoethyl)piperidine in one single step. The metal complexes [Zn(L)(Bpy)]NO₃ (<b>1</b>), [Cu(L)(Bpy)]NO₃ (<b>2</b>), and [Co(L)(Bpy)]NO₃ (<b>3</b>) were prepared by tethering <b>HL</b> and 2,2′-bipyridine. The synthesized <b>HL</b> and metal complexes <b>1–3</b> were thoroughly characterized using spectroscopic techniques such as ¹H NMR, ¹³C NMR, FTIR, EI-MS, molar conductance, and magnetic moment, in addition to CHN elemental analysis. The geometry of complexes was square pyramidal around the metal ions {Zn(II), Cu(II), and Co(II)}. The interaction of ligand and metal complexes with DNA and BSA macromolecules was accomplished by UV–Vis absorption and fluorescence spectroscopy in vitro. The hyperchromism in band at 303–325 with no shift supports the groove binding with some partial intercalation in grooves. Similarly, in BSA-binding studies, complex <b>2</b> shows greater binding potential in the hydrophobic core probably near the Trp-212 in the subdomain IIA. Furthermore, complex <b>2</b> shows excellent cytotoxicity on HepG2 cancer cells with IC₅₀ = 25.0 ± 0.45 µM. The detailed analysis by cell-cycle studies shows cell arrest at the G2/M phase. The type of cell death was authenticated by an annexin V-FTIC dual staining experiment that reveals maximum death by apoptosis together with non-specific necrosis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260479","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, synthesis, bioactivity and action mechanism of N-substituted N′-phenylpicolinohydrazides against phytopathogenic fungi","authors":"Yuhao Zhang, Ruofei Bai, Tengyi Du, Yiwei Wang, Bohang Zhou, Congwei Zhou, Le Zhou","doi":"10.1007/s11030-024-10984-9","DOIUrl":"https://doi.org/10.1007/s11030-024-10984-9","url":null,"abstract":"<p><i>N</i>′-phenylpicolinohydrazide has been proven to be a promising lead compound for research and development of novel fungicides for agriculture in our previous study. As our continuing research, in this study, a series of <i>N</i>-substituted derivatives of <i>N</i>′-phenylpicolinohydrazide were synthesized and explored for the inhibition activity on nine phytopathogenic fungi and action mechanism. The results found that eleven of the compounds had excellent antifungal activity with more than 80% inhibition rates at 50 <i>µ</i>g/mL on part or most of the fungi, especially <i>A. solani</i> and <i>P. piricola</i>. Compounds <b>5i</b>, <b>5j</b> and <b>5k</b> showed EC₅₀ values of &lt; 8.0 µg/mL against <i>A. solani</i> superior to positive control carbendazim (EC₅₀ = 36.0 µg/mL) while <b>5p</b> and <b>5q</b> exhibited the highest activity with EC₅₀ values of 2.72 and 2.80 µg/mL against <i>P. piricola</i> superior to positive control boscalid (EC₅₀ &gt; 50.0 µg/mL). Furthermore, <b>5k</b> also showed significant protective effect against <i>A. solani</i> infection on tomatoes in a concentration-dependent manner. Action mechanism research showed that <b>5k</b> was able to increase the intracellular ROS level, change both MMP and permeability of cell membrane and damage mycelial morphology. Molecular docking studies showed that <b>5k</b> could bind into ubiquinone-binding region of succinate dehydrogenase by hydrogen bonds, π-cation, π–π stacked, π-alkyl, and alkyl interactions. Additionally, the antibacterial activity was also investigated. Thus, <i>N</i>-substituted derivatives of <i>N</i>′-phenylpicolinohydrazide were emerged as novel and highly promising antifungal molecular skeletons to develop new fungicides for crop protection.</p><h3 data-test=\"abstract-sub-heading\">Graphic abstract</h3>\u0000","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260480","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":"AI and ML for small molecule drug discovery in the big data era II","authors":"Kunal Roy","doi":"10.1007/s11030-024-10983-w","DOIUrl":"10.1007/s11030-024-10983-w","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278585","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":"Environmental pollutant Di-(2-ethylhexyl) phthalate induces asthenozoospermia: new insights from network toxicology","authors":"Lei Xu, Menghua Shi, Guozheng Qin, Xuyao Lin, Bin Huang","doi":"10.1007/s11030-024-10976-9","DOIUrl":"https://doi.org/10.1007/s11030-024-10976-9","url":null,"abstract":"<p>The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178094","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":"An overview: total synthesis of arborisidine, and arbornamine.","authors":"Gitanjali Yadav, Megha, Sangeeta Yadav, Ravi Tomar","doi":"10.1007/s11030-024-10978-7","DOIUrl":"https://doi.org/10.1007/s11030-024-10978-7","url":null,"abstract":"<p><p>Arborisidine and Arbornamine are two monoterpenoid indole alkaloids that were isolated from the Malayan Kopsia arborea plant. This review provides valuable information about the total and formal syntheses of these alkaloids. The synthesis strategies discussed in this review, such as Pictet-Spengler cyclization, chemo- and stereoselective oxidative cyclization, Michael/Mannich cascade process, and intramolecular N-alkylation, can be useful for developing new methods to synthesize these and other similar compounds.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144894","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, network pharmacology, and molecular dynamics reveal potent cyclopeptide inhibitors against dengue virus proteins.","authors":"Mohammed A Imam, Thamir A Alandijany, Hashim R Felemban, Roba M Attar, Arwa A Faizo, Hattan S Gattan, Vivek Dhar Dwivedi, Esam I Azhar","doi":"10.1007/s11030-024-10975-w","DOIUrl":"https://doi.org/10.1007/s11030-024-10975-w","url":null,"abstract":"<p><p>The dengue virus is a major global health hazard responsible for an estimated 390 million diseases yearly. This study focused on identifying cyclopeptide inhibitors for envelope structural proteins E, NS1, NS3, and NS5. Additionally, 5579 cyclopeptides were individually screened against the four target proteins using a machine learning-based quantitative structure-activity relationship model. Subsequently, the best 10 cyclopeptides from each protein were selected for molecular docking with their corresponding proteins. Moreover, the protein-peptide complexes with the highest affinity were subjected to a 100-ns molecular dynamics simulation. The protein-protein complexes exhibited superior structural stability and binding interactions. Based on the results of the MD simulation analyses, which included checking values for Root Mean Square Deviation, Root Mean Square Fluctuation, Principal Component Analysis (PCA), free energy landscapes, and energetic components, it was found that NS5-CP03714 complex is more stable and has stronger binding interactions than NS3-CP02054. PCA and free energy landscape plots have confirmed the higher conformational stability of NS5-CP03714. Analysis of the energetic components revealed that NS5-CP03714 (total binding energy = - 47.19 kcal/mol) exhibits more favorable interaction energies and overall binding energy compared to NS3-CP02054 (total binding energy = - 27.36 kcal/mol), suggesting a stronger and more stable formation of the complex. In addition, the drug-target network of two specific peptides (CP02950 and CP05582) and their associated target proteins were analyzed. This analysis revealed valuable information about their ability to target several proteins and their potential for broad-spectrum activity. Additional experimental investigations are necessary to validate these computational results and assess the efficacy of identified peptide inhibitors in biological systems.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124393","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":"Flavonol derivatives containing piperazine and quinoxaline fragments: synthesis and antifungal activity.","authors":"Yi Liu, Hui Xin, Yuhong Wang, Qing Zhou, Jiao Tian, Chunmei Hu, Xingping Luo, Haotao Pu, Wei Xue","doi":"10.1007/s11030-024-10977-8","DOIUrl":"https://doi.org/10.1007/s11030-024-10977-8","url":null,"abstract":"<p><p>A series of flavonol derivatives containing piperazine and quinoxaline had been designed and synthesized. The biological activity test results showed that some of the target compounds had good antifungal activity against various fungi. N5 had the best antifungal activity against Phomopsis sp (P.s.) and Phytophthora capsica (P.c.). The half maximal effective concentration (EC₅₀) was 12.9 and 25.8 μg/mL against P.s. and P.c., respectively, which were better than azoxystrobin (Az, 25.4 and 71.1 μg/mL). In addition, the protective and curative activities of N5 against kiwifruit were 85.9 and 67.0% at 200 μg/mL in vivo, which were better than that of Az (65.9 and 57.0%). The protective and curative activities against chili leaves were 80.6 and 66.5% at 200 μg/mL, which were better than that of Az (77.6 and 60.0%). The scanning electron microscopy (SEM) experiment showed that the action of N5 caused the mycelium to bend and fold, changed its morphology and caused damaged to the mycelium. Through the measurement of relative conductivity, leakage of cytoplasmic contents and determination of malondialdehyde (MDA) content indicated that N5 could damage the integrity of pathogenic fungal cell membranes, change the permeability of cell membranes, and affect the normal growth of mycelium.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118725","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":"Identification and validation of oxidative stress-related diagnostic markers for recurrent pregnancy loss: insights from machine learning and molecular analysis.","authors":"Hui Hu, Li Yu, Yating Cheng, Yao Xiong, Daoxi Qi, Boyu Li, Xiaokang Zhang, Fang Zheng","doi":"10.1007/s11030-024-10947-0","DOIUrl":"https://doi.org/10.1007/s11030-024-10947-0","url":null,"abstract":"<p><p>It has been recognized that oxidative stress (OS) is implicated in the etiology of recurrent pregnancy loss (RPL), yet the biomarkers reflecting oxidative stress in association with RPL remain scarce. The dataset GSE165004 was retrieved from the Gene Expression Omnibus (GEO) database. From the GeneCards database, a compendium of 789 genes related to oxidative stress-related genes (OSRGs) was compiled. By intersecting differentially expressed genes (DEGs) in normal and RPL samples with OSRGs, differentially expressed OSRGs (DE-OSRGs) were identified. In addition, four machine learning algorithms were employed for the selection of diagnostic markers for RPL. The Receiver Operating Characteristic (ROC) curves for these genes were generated and a predictive nomogram for the diagnostic markers was established. The functions and pathways associated with the diagnostic markers were elucidated, and the correlations between immune cells and diagnostic markers were examined. Potential therapeutics targeting the diagnostic markers were proposed based on data from the Comparative Toxicogenomics Database and ClinicalTrials.gov. The candidate biomarker genes from the four models were further validated in RPL tissue samples using RT-PCR and immunohistochemistry. A set of 20 DE-OSRGs was identified, with 4 genes (KRAS, C2orf69, CYP17A1, and UCP3) being recognized by machine learning algorithms as diagnostic markers exhibiting robust diagnostic capabilities. The nomogram constructed demonstrated favorable predictive accuracy. Pathways including ribosome, peroxisome, Parkinson's disease, oxidative phosphorylation, Huntington's disease, and Alzheimer's disease were co-enriched by KRAS, C2orf69, and CYP17A1. Cell chemotaxis terms were commonly enriched by all four diagnostic markers. Significant differences in the abundance of five cell types, namely eosinophils, monocytes, natural killer cells, regulatory T cells, and T follicular helper cells, were observed between normal and RPL samples. A total of 180 drugs were predicted to target the diagnostic markers, including C544151, D014635, and CYP17A1. In the validation cohort of RPL patients, the LASSO model demonstrated superiority over other models. The expression levels of KRAS, C2orf69, and CYP17A1 were significantly reduced in RPL, while UCP3 levels were elevated, indicating their suitability as molecular markers for RPL. Four oxidative stress-related diagnostic markers (KRAS, C2orf69, CYP17A1, and UCP3) have been proposed to diagnose and potentially treat RPL.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118726","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":"Identification of potential NUDT5 inhibitors from marine bacterial natural compounds via molecular dynamics and free energy landscape analysis.","authors":"Amit Dubey, Amer M Alanazi, Rima Bhardwaj, Andrea Ragusa","doi":"10.1007/s11030-024-10950-5","DOIUrl":"https://doi.org/10.1007/s11030-024-10950-5","url":null,"abstract":"<p><p>NUDIX hydrolase 5 (NUDT5) is an enzyme involved in the hydrolysis of nucleoside diphosphates linked to other moieties, such as ADP-ribose. This cofactor is vital in redox reactions and is essential for the activity of sirtuins and poly(ADP-ribose) polymerases, which are involved in DNA repair and genomic stability. It has been shown that NUDT5 activity can also influence NAD+ homeostasis, thereby affecting cancer cell metabolism and survival. In this regard, the discovery of NUDT5 inhibitors has emerged as a potential therapeutic approach in cancer treatment. In this study, we conducted a high-throughput virtual screening of marine bacterial compounds against the NUDT5 enzyme and four molecules were selected based on their docking scores. These compounds established strong interactions within the NUDT5 active site, with molecular analysis highlighting the key role of Trp^28A and Trp^46B residues. Molecular dynamics simulations over 200 ns indicated a stable behavior, in association with root mean square deviation values always below 3 Å, suggesting conformational stability. Free energy landscape analysis further supported their potential as NUDT5 inhibitors, offering avenues for novel therapeutic strategies against NUDT5-associated breast cancer.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118727","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}