Current medicinal chemistry最新文献

{"title":"Investigating the Mechanisms of Mitochondrial Dysfunction in Ischemic Stroke and Predicting Therapeutics Through Machine Learning and Integrated Bioinformatics.","authors":"Chao Qi, Feng Dong, Kai Yang, Yanfei Lv","doi":"10.2174/0109298673371220250809113736","DOIUrl":"https://doi.org/10.2174/0109298673371220250809113736","url":null,"abstract":"<p><strong>Introduction: </strong>Ischemic Stroke (IS) represents the most prevalent subtype of cerebrovascular disease, characterized by complex pathophysiological mechanisms that remain inadequately characterized, particularly concerning mitochondrial dysfunctions. These mitochondrial impairments are increasingly recognized as contributory factors in IS pathogenesis, emphasizing the need for further investigation into the underlying molecular mechanisms involved.</p><p><strong>Methods: </strong>In this study, we integrated transcriptomic datasets from the Gene Expression Omnibus (GEO) with the comprehensive MitoCarta3.0 mitochondrial proteome inventory to elucidate the role of dysregulated Mitochondrial-Related Genes (MRGs) in IS. We employed an advanced bioinformatics and machine learning pipeline, incorporating differential expression profiling alongside network-based prioritization using CytoHubba. Rigorous feature selection was conducted through LASSO regression, Support Vector Machine (SVM), and Random Forest (RF) algorithms to derive a robust core MRG signature. Our methodology included training and validation cohorts to construct diagnostic models, which were critically evaluated via Receiver Operating Characteristic (ROC) curves, nomograms, and calibration analyses.</p><p><strong>Results: </strong>Our analysis identified a seven-gene signature comprising DNAJA3, ACSL1, HSDL2, ECHDC2, ECHDC3, ALDH2, and PDK4, which demonstrated significant correlation with activated CD8+ T-cell and natural killer cell infiltration. Furthermore, integrative network analyses revealed intricate regulatory interactions among MRGs, microRNAs, and transcription factors. Notably, drug-target predictions indicated Bezafibrate as a promising therapeutic agent for modulating mitochondrial homeostasis in the context of IS.</p><p><strong>Discussion: </strong>These findings offer a novel framework for ischemic stroke diagnosis and therapy, yet their computational derivation underscores the need for thorough experimental validation of MRGs and drug candidates, along with the integration of diverse clinical data to confirm their real-world applicability.</p><p><strong>Conclusion: </strong>Our findings underscore mitochondrial dysfunction not only as a critical factor in IS pathogenesis but also as a viable therapeutic target. The identified MRG signature presents potential for clinical application in diagnostic and pharmacological strategies aimed at ameliorating ischemic injury. This study highlights the translational significance of systems biology approaches within cerebrovascular medicine, warranting further mechanistic exploration of mitochondrial-immune interactions in stroke pathology.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Cytotoxicity Evaluation, and Molecular Dynamics of 4-Thiazolidinone Derivatives: A Potential Path to EGFR-Targeted Anticancer Therapy.","authors":"Tomasz Szostek, Dagmara Otto-Ślusarczyk, Michał A Dobrowolski, Maciej Wiśniewski, Piotr Roszkowski, Daniel Szulczyk","doi":"10.2174/0109298673400295250913044755","DOIUrl":"https://doi.org/10.2174/0109298673400295250913044755","url":null,"abstract":"<p><strong>Introduction: </strong>Heterocyclic compounds remain cornerstones of contemporary drug discovery because their ring-embedded heteroatoms confer adaptable electronics, conformational flexibility, and a broad spectrum of biological activities. The skeleton structure of 4-thiazolidinone is present in many cytotoxically active compounds and is often used in the design of new antitumor agents. This study aimed to synthesize, characterize, and evaluate the anticancer potential of fifteen new (2-imino-4-oxo-1,3-thiazolidin- 5-yl)acetic acid derivatives.</p><p><strong>Method: </strong>Compounds were synthesized using a consistent synthetic route involving a reaction between a thiourea derivative and maleic anhydride, which formed the thiazolidin- 4-one ring through cyclization. The compounds were then categorized into three sets based on the attached heterocyclic rings (tryptamine, thiazole, and 1,2,4-triazole). The NMR and X-ray analysis followed the synthesis. Apoptotic effects, cell cycle arrest, IL-6 suppression, docking, and dynamics simulations were conducted. Preliminary cytotoxic activity was tested on metastatic colorectal cancer (SW620) and human breast adenocarcinoma (MDA-MB-231) cell lines using the MTT assay.</p><p><strong>Result: </strong>Compounds 5, 6, and 7 demonstrated notable selectivity indexes (4.73, 2.42, 4.16, respectively) and were further investigated for their mechanisms of action, revealing pro-apoptotic properties and the ability to induce cell cycle arrest. Additionally, compound 5 inhibited IL-6 secretion by 76%. in silico studies revealed the formation of an energetically stable complex between compound 5 and the EGFR crystal structure (min/- max binding affinities of -9.4|-8.0 kcal/mol, compared to the -7.71 kcal/mol for the native ligand).</p><p><strong>Discussion: </strong>This preliminary study provides compelling data on synthesized derivatives, but more advanced testing is needed to assess their therapeutic value fully. Compared with earlier reports on related thiazolidinone scaffolds, the present derivatives exhibit improved potency, clearer selectivity, and mechanistic features consistent with EGFR inhibition and cytokine modulation.</p><p><strong>Conclusion: </strong>These findings validate (2-imino-4-oxo-1,3-thiazolidin-5-yl)acetic acid as a privileged core for cytotoxic lead generation and indicate that strategic substitution with either a tryptamine moiety (compound 5) or a 1,2,4-triazole ring (compound 7) is particularly advantageous. These compounds are promising EGFR-targeting anticancer candidates, warranting further investigation.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetes and Skin Health: Insights into Autoimmunity, Metals, and AGE-Mediated Disorders.","authors":"Geir Bjørklund, Monica Butnariu, Leonard Gurgas, Tony Hangan","doi":"10.2174/0109298673372197250911050753","DOIUrl":"https://doi.org/10.2174/0109298673372197250911050753","url":null,"abstract":"<p><p>Diabetes mellitus (DM) significantly impacts systemic and skin health, with advanced glycation end-products (AGEs), metal imbalances, and immune dysfunction emerging as central drivers of skin-related complications. Furthermore, dysregulation of essential metals like zinc, copper, and iron exacerbates oxidative damage and immune dysfunction, fostering a detrimental skin environment. Autoimmune processes, increasingly recognized in both type 1 and type 2 DM, contributes towards dermatological conditions such as bullous pemphigoid and vitiligo. Emerging therapeutic strategies, including AGE inhibitors, chelation therapies, antioxidants, RAGE antagonists, and immune modulators, offers promising avenues for intervention. Advances in diagnostic tools, such as LC-MS/MS and ICP-MS, facilitate precise detection of AGEs and metal imbalances, paving the way for innovative therapies. This review underscores the importance of multidisciplinary approaches to address the rising burden of DM-related skin disorders and improve the quality of life of affected individuals.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Anti-Glioma Mechanisms of Oridonin: Network Pharmacology and Experimental Insights into EMT Pathways.","authors":"Shiliang Chen, Yiran Fei, Xiaoli Jin, Cong Wang, Shiyuan Tong, Yibo He, Changjiang Wu, Zhezhong Zhang","doi":"10.2174/0109298673390934250923111917","DOIUrl":"https://doi.org/10.2174/0109298673390934250923111917","url":null,"abstract":"<p><strong>Introduction: </strong>Gliomas are aggressive brain tumors with a poor prognosis and high recurrence. Oridonin, a traditional Chinese medicine, has shown potential in treating various cancers, but its role in glioma treatment, especially in modulating Epithelial- Mesenchymal Transition (EMT), remains underexplored.</p><p><strong>Methods: </strong>We identified 371 potential target genes of Oridonin using various bioinformatics databases. Enrichment analyses, including Differential Expression Analysis, Gene Set Enrichment Analysis (GSEA), and Weighted Gene Co-expression Network Analysis (WGCNA), were performed to link these targets to glioma characteristics. in vitro experiments validated Oridonin's impact on EMT-related gene expression in glioma cells.</p><p><strong>Results: </strong>Enrichment analyses identified 19 common genes between Oridonin and glioma targets, with 12 EMT-related core genes. KEGG enrichment highlighted PI3K-Akt, MAPK pathways, and glioma pathways, while DO enrichment included high-grade gliomas. CCK8 assay showed Oridonin IC50 values of 6.92 μM for H4 and 10.54 μM for SW1783 glioma cell lines. WB results indicated increased E-Cadherin and decreased Vimentin, N-Cadherin, and Snail expression after Oridonin treatment. PPI network and single- cell transcriptome analyses identified key genes linked to glioma progression and immune cell infiltration.</p><p><strong>Discussion: </strong>Oridonin may inhibit glioma progression by targeting EMT-related pathways like PI3K-Akt and MAPK. The upregulation of E-Cadherin and downregulation of Vimentin, N-Cadherin, and Snail suggest a reversal of the EMT process. Future work should validate these effects in vivo and explore Oridonin's ability to cross the blood- -brain barrier.</p><p><strong>Conclusion: </strong>Oridonin may provide a novel therapeutic approach for glioma by targeting EMT-related pathways, offering a foundation for further clinical investigation.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and its Analogues in Focus.","authors":"Busra Acar, Nihan Aktas Pepe, Aleksandra Zivkovic, Holger Stark, Alaattin Sen","doi":"10.2174/0109298673435364251002112630","DOIUrl":"https://doi.org/10.2174/0109298673435364251002112630","url":null,"abstract":"<p><strong>Introduction: </strong>The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.</p><p><strong>Methods: </strong>hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.</p><p><strong>Results: </strong>IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti- MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-κB, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNFα (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.</p><p><strong>Discussion: </strong>The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.</p><p><strong>Conclusion: </strong>The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Side Chain Effects on the Lipophilicity-antimicrobial-toxicity Correlation of Greener 4-Alkoxy/Amino-7-Chloroquinolines.","authors":"Gabriela F Fiss, Everton P Silva, Maria F S Madruga, Abraão P Sousa, Helivaldo D S Souza, Rádamis B Castor, Maria H Nascimento, Krystyna G Lira, Petrônio F Athayde-Filho","doi":"10.2174/0109298673372039250614231629","DOIUrl":"https://doi.org/10.2174/0109298673372039250614231629","url":null,"abstract":"<p><strong>Background: </strong>More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.</p><p><strong>Objective: </strong>To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.</p><p><strong>Methods: </strong>4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SNAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their in silico ADMET test, in vitro antimicrobial activity against Gram-(+) and Gram-(-) bacteria, and Candida albicans fungus, and in vitro toxicity on Artemia salina larvae.</p><p><strong>Results: </strong>4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against Pseudomonas aeruginosa for 4-amino-7-chloroquinolines 6-8, with halos greater than 20 mm, and against C. albicans for 4-amino-7-chloroquinolines 1-3, with halos close to 30 mm. A correspondence between Minnow toxicity prediction and in vitro toxicity on A. salina larvae was observed, where compounds 3 and 14, with R = Pent, were both predicted to have high acute toxicity (log LC50 < -0.3) and classified as highly toxic (LC50 < 100 μg mL-1). It seems that increased lipophilicity in the side chain is harmful to A. salina larvae.</p><p><strong>Conclusion: </strong>Considering the results for compounds 1-3 and 6-8 with greater activity against C. albicans and P. aeruginosa, respectively, especially for 4-amino-7-chloroquinolines 6 and 7, which are slightly toxic on A. salina larvae (LC50 500-1000 μg mL-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of an E3 Ubiquitin Ligase Gene Model to Predict the Prognosis of Idiopathic Pulmonary Fibrosis Patients Using Integrated Bioinformatics Analysis.","authors":"Junhui Liu, Longfei Zhu, Guirong Li, Jingyu Chen","doi":"10.2174/0109298673380428250903105810","DOIUrl":"https://doi.org/10.2174/0109298673380428250903105810","url":null,"abstract":"<p><strong>Introduction: </strong>Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease and currently has limited treatment options. E3 ubiquitin ligases play a role in multiple diseases; however, there are few studies involving them in the development of IPF. This study aimed to develop an E3 ubiquitin ligase gene-based risk signature model to predict the prognosis of patients with IPF.</p><p><strong>Methods: </strong>We downloaded the GSE70866 dataset and the E3 ubiquitin ligase genes from the GEO database and the iUUCD database, respectively. We then used LASSO and multivariate Cox regression analysis to develop a prognostic signature model and validated its efficacy using the GEO dataset. Functional enrichment analysis, immune cell infiltration, and consensus clustering analysis were performed based on the model. Transcription factors associated with the genes in the model were identified using the hTFtarget database. scRNA-seq analysis identified key cell types through the analyses of cell communication and differentiation trajectories. The expression of the E3 genes in the model was detected by Western blot.</p><p><strong>Results: </strong>A prognostic model based on 5 E3 ubiquitin ligase genes (CDCA3, TRIM47, SH3RF1, SPAG16, LONRF3) was developed. The high expression of CDCA3, TRIM47, and SH3RF1 predicts the poor prognosis of IPF patients. Functional enrichment analysis indicated the functional difference between high- and low-risk groups. And the model is enriched in the signaling pathway related to fibrosis. Immune cell infiltration analysis revealed 22 immune cell types related to the model differed significantly between the two risk groups. Single-cell RNA analysis revealed that alveolar epithelial cells (AEC) have a strong interaction with macrophages, based on the model and the potential role of the 5 E3 ligase genes in IPF. Finally, the western blot results demonstrated that CDCA3, SH3RF1, and TRIM47 were expressed at higher levels in the model with IPF compared to normal, while SPAG16 was expressed at lower levels in IPF.</p><p><strong>Discussion: </strong>In this study, the prognostic model constructed using the data from the GEO database significantly improved the accuracy of individualized prognosis prediction in patients with pulmonary fibrosis. The high-risk populations identified by this model may benefit from early intervention, providing an objective tool for informed clinical decision-making. In addition, the strong predictive signatures in the model suggest its potential pathological mechanism value, which points out the direction for future targeted research.</p><p><strong>Conclusion: </strong>Our study highlights the E3 ubiquitin ligase gene-based risk model as a promising tool for enhancing prognostic accuracy in IPF.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imidazole-2-thione and Acylhydrazone Derivatives Targeting Carbonic Anhydrase-II: Synthesis, In-Vitro Evaluations, and MM-GBSA Calculation.","authors":"Muhammad Ibrahim, Sobia Ahsan Halim, Majid Khan, Ajmal Khan, Muhammad Waqas, Manzoor Ahmad, Nazia Akbar, Sajid Ali, Samee Ullah, Jalal Uddin, Abdul Latif, Mumtaz Ali, Ahmed Al-Harrasi","doi":"10.2174/0109298673365555250617114928","DOIUrl":"https://doi.org/10.2174/0109298673365555250617114928","url":null,"abstract":"<p><strong>Introduction: </strong>Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma.</p><p><strong>Objectives: </strong>This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[ d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13).</p><p><strong>Methods: </strong>In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole- 2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II).</p><p><strong>Results: </strong>Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 μM), such as compounds 1 (IC50: 10.5±0.81 μM), 2 (IC50: 11.3±0.36 μM), 3 (IC50: 16.5±0.53 μM), 4 (IC50: 15.8±1.02 μM), 5 (IC50: 13.7±1.03 μM), and 9 (IC50: 12.2±1.03 μM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 μM) exhibited the highest and compound 6 (IC50: 27.6±0.39 μM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II.</p><p><strong>Conclusion: </strong>These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boswellic acid derived molecules as SARS-CoV-2 spike protein inhibitors: A comprehensive virtual screening, triplicate molecular dynamic simulation and biochemical validation.","authors":"Atta Ullah, Muhammad Waqas, Saeed Ullah, Sobia Ahsan Halim, Satya Kumar Avula, Sadeeq Ur Rehman, Najeeb Ur Rehman, Magda H Abdellattif, Ajmal Khan, Ahmed Al-Harrasi","doi":"10.2174/0109298673354901250402143533","DOIUrl":"https://doi.org/10.2174/0109298673354901250402143533","url":null,"abstract":"<p><strong>Background: </strong>Coronavirus disease (COVID-19) is a highly infective disease caused by SARS-CoV-2. The SARS-CoV-2 spike protein binds with the human ACE2 receptor to facilitate viral entry into the host cell; therefore, spike protein serves as a potential target for drug development.</p><p><strong>Objective: </strong>Keeping in view the significance of SARS-CoV-2 spike protein for viral replications, in the current study, we identified the potent inhibitors against SARS-CoV-2 spike protein in order to combat the viral infection.</p><p><strong>Methods: </strong>In the current study, we screened an in-house library of ~900 natural and synthesized compounds against the spike protein receptor binding domain (RBD) using a structure-based virtual approach, followed by an in-vitro inhibition bioassay.</p><p><strong>Results: </strong>Seven (C1-C7) potent compounds were identified with docking scores ≥ -6.66 Kcal/mol; their drug-likeness, pharmacokinetic, and pharmacodynamic characteristics were excellent with no toxic effect. Those molecules were subjected to a triplicate simulation for 200 ns, which further confirmed their stable binding with RBD. This tight packing of complexes was reflected by calculated binding free energy, which disclosed higher binding free energy of C4, C7 and C6 than C1-C3, while predicted entropic energy demonstrates higher values for C4, C7 and C1 than the rest of the compounds, indicating more thermodynamic stability in protein due to conformational changes in spike protein induced by binding of C4, C7 and C1. These computational analyses were later validated through in-vitro bioassay. Remarkably, C2-C7 displayed significant inhibitory potential with >76 to 89 % inhibition and C3, C4, C6 and C7 demonstrated the highest inhibition of RBD.</p><p><strong>Conclusion: </strong>The current findings suggest that compounds C3 and C6 effectively disrupt the function of RBD of SARS-CoV-2 spike protein and can serve as potential drug candidates for spike protein.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically Predicted Gastroesophageal Reflux Disease and Common Thyroid Disorders: A Two-sample Mendelian Randomization Study.","authors":"Hanxin Lv, Xinyu Yang, Ruting Zhang, Yuyang Xie, Xiaohan Ni, Xiaoqin Yang, Bimin Shi","doi":"10.2174/0109298673362752250730045645","DOIUrl":"https://doi.org/10.2174/0109298673362752250730045645","url":null,"abstract":"<p><strong>Introduction: </strong>The causality between thyroid disorders and Gastroesophageal Reflux Disease (GERD) remains to be deciphered. This two-sample Mendelian Randomization (MR) study was performed to elucidate the causal association between GERD and thyroid diseases and functions.</p><p><strong>Methods: </strong>Summary statistics for GERD were retrieved from a published GWAS dataset deposited in the Integrative Epidemiology Unit OpenGWAS database. Thyroid hormone level data were obtained from the ThyroidOmics Consortium, and genetic variants associated with thyroid disorders were sourced from the FinnGen Project. MR statistical analyses used the Inverse Variance Weighted (IVW) algorithm, followed by various sensitivity and reliability analyses. Odds Ratio (OR) and beta coefficient (β) with 95% Confidence Interval (CI) were estimated for categorical and continuous outcomes, respectively. The significant causal association was determined based on a Bonferroni-corrected threshold of p-value < 0.0021 (calculated as 0.05/24 trait pairs).</p><p><strong>Results: </strong>The findings of MR analysis tend to favor the causality of GERD for hyperthyroidism (IVW: OR = 1.517, 95% CI: 1.164 to 1.978, p = 2.04E-03) but not the other thyroid disorders. The reverse MR estimates suggested that thyroid disorders may not affect the susceptibility of GERD. Moreover, genetic proxied GERD was significantly negatively associated with circulating Thyroid Stimulating Hormone (TSH) level (IVW: β = -0.048, 95% CI: -0.078 to -0.019, p = 1.17E-03), whereas the causality of this enteropathy on Free Triiodothyronine (FT3), Free Thyroxine (FT4), Total Triiodothyronine (TT3), FT3/FT4 ratio, and TT3/FT4 ratio (and vice versa) is unfounded.</p><p><strong>Discussion: </strong>This MR study indicates that the genetic liability to GERD is significantly detrimental to hyperthyroidism risk and the homeostasis of TSH.</p><p><strong>Conclusion: </strong>The findings suggest that effective GERD management could mitigate hyperthyroidism risk.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}