Molecular Diversity最新文献

{"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}

{"title":"Ligand and structure-based virtual screening approaches in drug discovery: minireview.","authors":"Matheus Nunes da Rocha, Damião Sampaio de Sousa, Francisco Rogenio da Silva Mendes, Helcio Silva Dos Santos, Gabrielle Silva Marinho, Márcia Machado Marinho, Emmanuel Silva Marinho","doi":"10.1007/s11030-024-10979-6","DOIUrl":"https://doi.org/10.1007/s11030-024-10979-6","url":null,"abstract":"<p><p>The compilation of ligand and structure-based molecular modeling methods has become an important practice in virtual screening applied to drug discovery. This systematic review addresses and ranks various virtual screening strategies to drive the selection of the optimal method for studies that have as their starting point a multi-ligand investigation and investigation based on the protein structure of a therapeutic target. This study shows examples of applications and an evaluation based on the objective and problematic of a series of virtual screening studies present in the ScienceDirect® database. The results showed that the molecular docking technique is widely used in scientific production, indicating that approaches that use protein structure as a starting point are the most promising strategy for drug discovery that relies on virtual screening-based research.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of sulfonamide derivatives containing imidazole moiety as ALK5 inhibitors.","authors":"Shu-Yan Ding, Yu-Xuan Yang, Chuang Liu, Xu-Yin Quan, Zi-Han Zhao, Cheng-Hua Jin","doi":"10.1007/s11030-024-10973-y","DOIUrl":"https://doi.org/10.1007/s11030-024-10973-y","url":null,"abstract":"<p><p>Four series of sulfonamide derivatives (13a-b, 14a-d, 15a-b, and 16a-d) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC₅₀ = 0.130 μM) and 15a (IC₅₀ = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299. Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103266","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":"Combination of ligand‑based and structure‑based virtual screening for the discovery of novel Janus kinase 2 inhibitors against philadelphia-negative myeloproliferative neoplasms.","authors":"Binyou Wang, Jianmin Guo, Bo Chen, Yan Jiao, Ying Wan, Jianming Wu, Yiwei Wang","doi":"10.1007/s11030-024-10938-1","DOIUrl":"https://doi.org/10.1007/s11030-024-10938-1","url":null,"abstract":"<p><p>The activating V617F mutation in Janus kinase 2 (JAK2) has been shown to be the major cause for classic Philadelphia-negative myeloproliferative neoplasms (MPNs). Thus, the development of pharmacologic JAK2 inhibitors is an essential move in combating MPNs. In this study, screening methods examining both ligands and their structures were developed to discover novel JAK2 inhibitors from the ChemDiv database with virtual screening identifying 886 candidate inhibitors. Next, these compounds were further filtered using ADMET, drug likeliness, and PAINS filtering, which reduced the compound number even further. This consolidated list of candidate compounds (n = 49) was then evaluated biologically at molecular level and the highest performing inhibitor with a novel scaffold was selected for further examination. This candidate inhibitor, CD4, was then subjected to molecular dynamics studies, with complex stability, root-mean-square deviation, radius of gyration, binding free energy, and binding properties all examined. The result suggested that CD4 interacts with JAK2 and that the CD4-JAK2 complex is stable. This study was able to identify a candidate inhibitor that warrants further examination and optimization and may potentially serve as a future MPN treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, crystal structure, Hirshfeld surface, computational and biological studies of spiro-oxindole derivatives as MDM2-p53 inhibitors.","authors":"Monisha Sivanandhan, Sutha Ragupathy, Arumugam Thangamani, Amutha Parasuraman","doi":"10.1007/s11030-024-10974-x","DOIUrl":"https://doi.org/10.1007/s11030-024-10974-x","url":null,"abstract":"<p><p>The spiro-oxindole derivatives were synthesized via a 1,3-dipolar cycloaddition approach and characterized by FT-IR, ¹H, ¹³C NMR and mass spectral techniques. The single crystal XRD of 6d further validates the formation of compounds. DFT calculations indicated the reactive nature of compound 6d. Docking studies with 5LAW disclosed the minimum binding energy of - 10.83 kcal/mol for 6d. Furthermore, safe oral bioavailability was ensured by the physicochemical, pharmacokinetic, and toxicity predictions. The anticancer analysis of synthesized compounds showed substantial activity against A549 cells, notably with an IC₅₀ value of 8.13 ± 0.66 µM for 6d compared to standard doxorubicin. 6d was also evaluated for cytotoxicity against L929 healthy cells and A549, showing selectivity towards A549 than healthy cells. AO/EB staining method showed early apoptotic cellular death in the A549 cell line in a dose-dependent manner.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103267","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}