Combinatorial chemistry & high throughput screening最新文献

{"title":"Corrigendum to: Network Pharmacology and Computational Study to Identify Active Components and Potential Targets of Polygonatum sibiricum for Hepatocellular Carcinoma Treatment.","authors":"Yuan Pan, Xiaoyu Zhang, Chao Chen, Chunmei Hu","doi":"10.2174/1386207329999260612091311","DOIUrl":"https://doi.org/10.2174/1386207329999260612091311","url":null,"abstract":"<p><p>We have identified that the funding statement in the published version of this article [1] was inadvertently published incorrectly. The revised section is provided below. The original article can be found online at https://www.benthamscience.com/article/151787. The publisher apologizes for any inconvenience caused. Details of the error and the correction are provided below. Original: FUNDING This study was supported by the Social Development Project of the Key Research and Development Plan of Jiangsu Province (BE2023660); Innovation center for infectious disease of Jiangsu Province (NO.CXZX202232), and \"333 talent project\" of Jiangsu Province. Corrected: FUNDING None.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263628","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":"Anshen Decoction Improves Synaptic Plasticity and Memory in Insomnia Rats by Regulating Hippocampal Mitochondrial Dysfunction via the AMPK/PGC-1α Pathway.","authors":"Tiantian Tan, Biyong Liu, Shaojie Wan, Bingqi Zhang, Haoming Mi, Chenlu Sun, Ruixin Zhang, Lei Jiang, Jianmin Liu, Xueqi Tan, Zhijie Li","doi":"10.2174/0113862073414239250928063751","DOIUrl":"https://doi.org/10.2174/0113862073414239250928063751","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigated the effects of Anshen Decoction (ASD) on heart-kidney disharmony insomnia, focusing on the AMPK/PGC-1α pathway.</p><p><strong>Methods: </strong>ASD components were analyzed via HPLC. A rat model of heart-kidney disharmony insomnia was established using compound stressors and p-chlorophenylalanine (PCPA). After intervention with ASD, Estazolam, or Wuling capsule (WL), behavioral tests were conducted. Serum levels of stress hormones-Corticotropin-Releasing Hormone (CRH), Adrenocorticotropic Hormone (ACTH), and Cortisol (CORT) were measured. Hippocampal ATP content and mitochondrial respiratory chain complexes III/IV (COX-III/COX-IV) activity were evaluated. HE and JC-1 staining detected histopathology and mitochondrial membrane potential (MMP). Synaptic plasticity proteins (GAP-43, PSD-95, SynI) and AMPK/PGC-1α pathway components were analyzed via Western blot and IHC.</p><p><strong>Results: </strong>Following ASD treatment, the learning and memory capabilities of model rats were significantly enhanced, anxiety and tension were alleviated, hippocampal pathological damage was mitigated, and serum levels of CRH, ACTH, and CORT were reduced. These findings were consistent with those observed in the two positive control groups treated with Estazolam and WL. Moreover, ASD treatment upregulated the levels of GAP-43, PSD-95, SynI, ATP, COX-III, and COX-IV in the hippocampal tissue of model rats, increased MMP levels, and elevated the p- AMPKα /AMPKα protein ratio as well as the expression levels of PGC-1α, NRF-1, and TFAM proteins.</p><p><strong>Conclusion: </strong>ASD can ameliorate learning and memory impairments in rats with heart-kidney disharmony insomnia. This effect may be attributed to the activation of the AMPK/PGC-1α axis, which inhibits mitochondrial dysfunction in the hippocampus and enhances synaptic plasticity.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257622","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":"Preclinical Research on Bacteriophage Therapy for Carbapenem-Resistant Klebsiella Pneumoniae: A Systematic Review.","authors":"Xiexue Liu, Ye Liang, Yu Li, Xinhua Qiang, Yibin Lin, Jie He","doi":"10.2174/0113862073443395260418195524","DOIUrl":"https://doi.org/10.2174/0113862073443395260418195524","url":null,"abstract":"<p><strong>Introduction: </strong>Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a substantial threat to global health. As the effectiveness of first-line antibiotics like tigecycline and polymyxins wanes, bacteriophage therapy, including phage cocktails and integrated approaches, has emerged as a feasible alternative. This systematic review evaluated the bactericidal efficacy of bacteriophages against carbapenem-resistant K. pneumoniae in preclinical studies.</p><p><strong>Methods: </strong>A comprehensive search of PubMed, Web of Science, and Embase databases was conducted for records published between January 2010 and December 2024. Risk of bias was assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE tool). Primary endpoints were animal mortality and tissue bacterial burden, reported as pooled Risk Ratios (RRs) and mean differences using random-effects models. The study was registered with PROSPERO (CRD420251018670).</p><p><strong>Results: </strong>Of 191 screened references, 18 studies met the selection criteria and were assessed as having low to moderate risk of bias. In animal infection models, subgroup analyses demonstrated a statistically significant association between bacteriophage therapy and reduced mortality in both murine (RR 0.30 (95% CI 0.22, 0.41), I2= 0.0%) and Galleria mellonella larva models (RR 0.36 (95% CI 0.16,0.81), I2= 23.7%), with no significant difference between subgroups (p= 0.689). The overall pooled analysis confirmed a significant reduction in mortality (RR 0.32 (95% CI 0.24,0.42), I2= 0.0%), indicating substantial improvement in infection outcomes. Bacteriophage therapy remained non-inferior to conventional antibiotic therapy for CRKP.</p><p><strong>Discussion: </strong>The findings substantiate the potent bactericidal activity of bacteriophage therapy against CRKP in preclinical settings, highlighting its feasibility and safety profile. The consistency of results across different animal models strengthens the evidence base. However, the translation of these promising results into clinical practice requires further validation. Limitations of this review include the relatively small number of available studies and occasional missing experimental details.</p><p><strong>Conclusion: </strong>Bacteriophage therapy exhibits significant potential as an effective intervention against CRKP infections in preclinical models. Future research should focus on expanding the sample size and rigor of preclinical studies to corroborate these findings and provide a robust foundation for clinical application.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257757","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":"Interleukin-35 Ameliorates Cyclophosphamide-induced Ovarian Injury by Inhibiting PANoptosis.","authors":"Yuhan Zhang, Wei Zhou, Jia Yu, Yuan Zhong, Yan Zhao, Qi Chen","doi":"10.2174/0113862073467540260321183320","DOIUrl":"https://doi.org/10.2174/0113862073467540260321183320","url":null,"abstract":"<p><strong>Introduction: </strong>Cyclophosphamide (CTX) is widely used in chemotherapy; however, its clinical application is frequently accompanied by gonadotoxic effects, which can result in impaired ovarian function and subsequent infertility in women. Consequently, effective strategies to mitigate chemotherapy-induced ovarian injury remain an important unmet need. Interleukin-35 (IL-35), a recently identified member of the IL-12 cytokine family, has been implicated in immune regulation and the maintenance of immune homeostasis. In parallel, accumulating evidence indicates that ovarian damage involves multiple forms of regulated cell death rather than a single apoptotic pathway. PANoptosis, an integrated cell-death program encompassing pyroptosis, necroptosis, and apoptosis, has recently emerged as a key mechanism in tissue injury. To date, whether IL-35 participates in CTX-induced ovarian injury and whether it modulates PANoptosisrelated pathways has not been clearly elucidated.</p><p><strong>Materials and methods: </strong>Female C57BL/6 mice were randomly divided into four groups: control, CTX treatment, IL-35 treatment, and combined CTX + IL-35 treatment. Histopathological alterations in ovarian tissue were assessed using hematoxylin and eosin staining, whereas ELISA, qRT-PCR, immunohistochemistry, and western blot assays were subsequently conducted to investigate potential molecular mechanisms.</p><p><strong>Results: </strong>IL-35 showed a protective effect against CTX-induced ovarian injury. Serum FSH levels were reduced. Serum E2 and AMH levels were increased. Ovarian histopathological structure was improved. CTX treatment increased oxidative stress markers. These markers included ROS, SOD, and MDA. CTX treatment increased apoptosis markers (Bax and Bcl2). CTX treatment increased pyroptosis markers (NLRP3 and IL-1β). CTX treatment increased necroptosis markers (p-MLK and p-RIPK1). IL-35 pretreatment reduced all listed molecular changes. Further analysis showed enhanced activation of the ovarian Nrf2/HO-1 signaling pathway after IL-35 pretreatment during CTX exposure.</p><p><strong>Discussion: </strong>IL-35 preserves ovarian reserve during CTX challenge by activating Nrf2/HO-1 to restore redox balance, thereby coordinately inhibiting pyroptosis, necroptosis, and apoptosis-key drivers of chemotherapy-induced follicular depletion.</p><p><strong>Conclusion: </strong>IL-35 reduced CTX-induced ovarian injury. This effect occurs through the regulation of oxidative stress and PANoptosis. These findings indicate the therapeutic potential of IL- 35 for ovarian injury caused by CTX.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223792","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":"A Review of the Pharmacodynamics and Pharmacokinetics of Albiflorin.","authors":"Qianyu Wang, Wenxia Xu, Jinyin Ye, Tongfei Jiang, Shan Xiong, Xiaoqiong Zhang","doi":"10.2174/0113862073455210260516223538","DOIUrl":"https://doi.org/10.2174/0113862073455210260516223538","url":null,"abstract":"<p><strong>Introduction: </strong>Albiflorin, a monoterpenoid glycoside extracted from Paeonia lactiflora, has garnered growing interest in both traditional Chinese medicine and contemporary pharmacological research owing to its extensive therapeutic potential. However, a systematic understanding of its pharmacological activities and pharmacokinetic characteristics profile is still lacking.</p><p><strong>Methods: </strong>An integrative literature review was conducted using major biomedical databases to collect experimental and pharmacokinetic evidence related to albiflorin. The data were synthesized to evaluate their pharmacological activities, signaling mechanisms, and absorption, distribution, metabolism, and excretion (ADME) behavior.</p><p><strong>Results: </strong>Albiflorin demonstrated broad pharmacological effects, including anti-inflammatory, neuroprotective, psychotropic, antitumor, metabolic modulatory, bone-protective, cardiovascular, analgesic, and hepatoprotective activities.</p><p><strong>Discussion: </strong>These pharmacological functions were associated with coordinated modulation of key signaling cascades, notably NF-κB/MAPK and PI3K/AKT. Pharmacokinetic investigations indicated rapid absorption and extensive tissue distribution, while oral bioavailability remained suboptimal but amenable to formulation-based enhancement.</p><p><strong>Conclusion: </strong>Albiflorin represents a promising multifunctional natural compound with wide therapeutic prospects. Further mechanistic studies, pharmaceutical optimization, and clinical validation are required to advance its clinical translational application.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223840","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":"Unraveling the Role of miR-33a-5p in Bladder Cancer Progression: Clinical Significance and Functional Pathways.","authors":"Guizhen Lyu, Dongbing Li","doi":"10.2174/0113862073416746251021104915","DOIUrl":"https://doi.org/10.2174/0113862073416746251021104915","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigates the expression patterns, clinical relevance, and mechanisms of miR-33a-5p in bladder cancer (BLCA) to evaluate its role as a prognostic biomarker and therapeutic target.</p><p><strong>Methods: </strong>We analyzed miR-33a-5p expression data from the TCGA-BLCA dataset, and correlated expression levels with clinical features using statistical methods such as the Wilcoxon rank-sum test and logistic regression. Kaplan-Meier and Cox regression analyses were used to evaluate miR-33a-5p's prognostic impact. Bioinformatics tools identified potential targets, and qRTPCR validated miR-33a-5p overexpression in BLCA cell lines.</p><p><strong>Results: </strong>miR-33a-5p was significantly overexpressed in BLCA tissues compared to normal tissues (P < 0.001), and its high expression was associated with radiation therapy (P = 0.036). Elevated miR-33a-5p expression predicted worse overall survival (HR: 1.37, 95% CI: 1.02-1.84, P = 0.035), disease-specific survival (HR: 1.69, 95% CI: 1.18-2.42, P = 0.004), and progression-free survival (HR: 1.48, 95% CI: 1.10-1.98, P = 0.01). Bioinformatics analysis identified 96 overlapping genes regulated by miR-33a-5p, involved in cardiomyopathy and calcium signaling pathways. qRT-PCR confirmed significant upregulation of miR-33a-5p in BLCA cell lines versus normal urothelial cells (P < 0.001).</p><p><strong>Discussion: </strong>The study highlights miR-33a-5p as an independent prognostic biomarker for BLCA, with potential roles in tumor progression through multiple pathways. These findings build upon previous studies in cancers such as lung and colon and underscore their therapeutic relevance in BLCA. While miR-33a-5p emerges as an independent prognostic factor, functional studies are warranted to clarify its mechanisms.</p><p><strong>Conclusion: </strong>miR-33a-5p is a promising prognostic biomarker and potential therapeutic target for BLCA, with implications for risk stratification and targeted therapy in BLCA management.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197625","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":"A Multimodal Deep Learning Model for Objective Identification of Sub-health Status in Traditional Chinese Medicine.","authors":"Diankun Cui, Yue Meng, Jinlian Liu, Lingru Li, Yanfei Zheng, Ruoxi Yu, Yifan Xia, Shujuan Hou, Qi Wang","doi":"10.2174/0113862073484389260528213445","DOIUrl":"https://doi.org/10.2174/0113862073484389260528213445","url":null,"abstract":"<p><strong>Introduction: </strong>Sub-health is an intermediate state between health and disease. Early diagnosis in clinical practice is difficult, which delays timely intervention. Traditional Chinese Medicine (TCM) constitution theory divides sub-health into eight categories; however, existing diagnostic tools mainly focus on psychological assessment and lack objective phenotypic indicators. Multimodal technology provides a new direction for the objective diagnosis of sub-health by integrating objective human phenotypic images with expert experience.</p><p><strong>Methods: </strong>Tongue images, facial images, and infrared thermal images were collected from 1389 participants. In the pre-experiment, Model-1 consisted of a ResNet-18 network, an extended binary classification strategy, and a cross-attention fusion mechanism. Model-2 was developed based on Model-1 by integrating expert experience via Qwen2.5 using structural prompting. Accuracy, recall, precision, specificity, and AUC were used to evaluate model performance.</p><p><strong>Results: </strong>The overall performance of Model-1 was good, with most core indicators of body constitution exceeding 0.7. However, PDC (accuracy 0.722, AUC 0.682) and QDC (accuracy 0.732, AUC 0.705) showed relatively poor performance, characterized by high recall but low specificity. The core indicators of Model-2 improved further. Notably, PDC (accuracy 0.772, AUC 0.732) and QDC (accuracy 0.778, AUC 0.756) were significantly improved, and the imbalance between recall and specificity was also alleviated.</p><p><strong>Discussion: </strong>Multimodal fusion is critical for improving classification performance in TCM constitution recognition. The reasonable integration of clinical expert experience effectively optimizes feature fusion efficacy, highlighting the indispensable value of empirical expertise. Rooted in the empirical characteristics of TCM, embedding expert knowledge into the data-driven framework further enhances the robustness and credibility of the screening model.</p><p><strong>Conclusion: </strong>This study established an expert experience-enhanced multimodal model for subhealth and TCM constitution identification. The model achieves objective quantification and accurate classification of sub-health states, providing a valuable technical reference for population health management and early sub-health risk screening.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197643","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":"Integrated Network Pharmacology, Molecular Docking, and Experimental Validation for Uncovering the Pharmacodynamic Basis of Sanghuang against Human Pulmonary Fibrosis.","authors":"Hongyan Lin, Shuaijun Cui, Wenxue Sun, Mengmeng Liu, Xinghong Li, Bangmei Ye, Jing Xu","doi":"10.2174/0113862073479233260422055149","DOIUrl":"https://doi.org/10.2174/0113862073479233260422055149","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction/objective: &lt;/strong&gt;Sanghuang, a traditional Chinese medicinal fungus, exhibits well-documented anti-inflammatory, antioxidant, and antitumor activities. Emerging preclinical evidence indicates its efficacy in ameliorating bleomycin-induced Pulmonary Fibrosis (PF) in murine models. However, the molecular mechanisms mediating its anti-fibrotic effects remain poorly elucidated. This study was designed to systematically identify the bioactive constituents, pharmacological targets, and regulatory signaling networks that mediate the anti-PF effects of Sanghuang.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A bleomycin-induced mouse PF model was established to evaluate the in vivo therapeutic efficacy of Sanghuang. Integrative network pharmacology was applied to predict Sanghuang-derived bioactive compounds and their putative targets, followed by PF-related target screening and machine learning-based prioritization of high-confidence anti-fibrotic targets. Protein-Protein Interaction (PPI) network construction and GO/KEGG enrichment analyses were performed to identify key anti-fibrotic components and signaling pathways. Molecular docking and molecular dynamics simulations were conducted to evaluate the binding affinity and stability of prioritized constituents with core targets. In vitro functional validation was performed in TGF-β-stimulated A549 cells to assess the effects of stigmastane-3,5,6-triol on Epithelial-Mesenchymal Transition (EMT) and cell migration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Sanghuang treatment significantly alleviated bleomycin-induced histopathological damage and collagen deposition in lung tissues. Integrated network pharmacology and machine learning analyses identified 61 high-probability anti-PF targets and 20 candidate bioactive compounds, among which stigmastane‑3,5,6‑triol and genkwanin exhibited prominent multi‑target binding potential. ARG1, BCHE, MAOA, and MMP8 were recognized as core hub targets. Stigmastane‑3,5,6‑triol displayed strong predicted binding affinity and stable complex formation with these four core targets. KEGG pathway enrichment analysis revealed significant enrichment in AGE/RAGE, PI3K/AKT, and MAPK signaling cascades. Functionally, stigmastane‑3,5,6‑triol dose‑dependently reversed TGF‑β‑induced EMT by restoring E‑cadherin expression, suppressing the upregulation of N‑cadherin and vimentin, and inhibiting cell migration, with favorable in silico ADMET properties.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Stigmastane-3,5,6-triol may be a key anti-fibrotic constituent of Sanghuang, exerting its therapeutic effects through high-affinity multi-target interactions with ARG1, MAOA, MMP8, and BCHE, as well as by inhibiting EMT. Among these targets, ARG1, MAOA, and MMP8 are critically implicated in PF pathogenesis, whereas BCHE represents a novel, under-investigated target warranting further experimental validation. Mechanistically, the anti-fibrotic activity of Sanghuang is achieved through the coordinated ","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136893","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":"Identification and Characterization of New Therapeutic Candidates for Naegleria fowleri- brain-eating Amoeba: A Multi-target Approach Based on 3D-QSAR, Molecular Docking, MM-GBSA, ADMET and Molecular Dynamics.","authors":"Nadia Noor, Shagufta Parveen, Maryam Rashid, Nusrat Shafiq, Amina Sardar, Salim S Al-Rejaie, Lei Zhang, Mohamed Mohany","doi":"10.2174/0113862073349316250401072754","DOIUrl":"https://doi.org/10.2174/0113862073349316250401072754","url":null,"abstract":"<p><strong>Background: </strong>Naegleria fowleri is the most destructive and common brain-eating amoeba because it badly affects the human Central Nervous System (CNS), when amoeba in water goes up into the nose. N. fowleri also leads to PAM (primary amoebic meningoencephalitis) in humans. The lack of effective therapies for the treatment of PAM is a great drawback. The synthesis of new drug candidates for the treatment of this disease is time consuming and costly process.</p><p><strong>Aims & objectives: </strong>Therefore, to reduce time and cost, already FDA-approved brain cancer drugs can be repurposed to get an effective drug for the management of Naegleria fowleri because compounds used to treat brain cancer also have antiviral activities.</p><p><strong>Methods: </strong>For this purpose, an appropriate three-dimensional (3D-QSAR) model was created using the IC50 values of anti-brain cancer drugs. The QSAR (quantitative structure activity relationship) can provide suitable input for determining the structure of brain cancer drugs against Naegleria fowleri. The model validation was used as statistical parameters like r2 and q2.</p><p><strong>Results: </strong>An appropriate 3D-QSAR was carried out with q2 and r2 calculated values like 0.9935 and 0.7249. The model QSAR also showed the predicted activities of various currently available and new drugs for brain cancer. The study was followed by molecular docking and MD simulation.</p><p><strong>Discussion: </strong>The results of docking study revealed that the protein 6W7G shows a high binding affinity with Harmol, the most active compound. MD simulation of 6G6R protein showed an RMSD value of about 0.35 Å.</p><p><strong>Conclusion: </strong>The present study indicated that the drug harmol could be an effective treatment for PAM in consideration of the 3D-QSAR, molecular docking, MD and ADME and toxicity analysis. However, further in vivo and in vitro studies are in process for the approval of this drug for the management of Naegleria fowleri.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136827","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":"AI-Driven De novo Design of HDAC6/EZH2 Dual-target Peptide Inhibitors for Epigenetic Cancer Therapy.","authors":"Yu Zhang, Si Chen, ShiJie Gai, Xiaoli Zhi","doi":"10.2174/0113862073444069260330163834","DOIUrl":"https://doi.org/10.2174/0113862073444069260330163834","url":null,"abstract":"<p><strong>Introduction: </strong>Histone deacetylase 6 (HDAC6) and enhancer of zeste homolog 2 (EZH2) are crucial epigenetic regulators in cancer, with their synergistic roles playing a significant part in tumorigenesis and progression. However, dual-target peptide inhibitors that target both HDAC6 and EZH2 have not yet been developed. In this work, we present an AI-driven de novo design strategy to develop novel peptide inhibitors that target HDAC6 and EZH2.</p><p><strong>Methods: </strong>Our approach used RFDiffusion to generate diverse peptide conformations, followed by ProteinMPNN to predict the most probable amino acid sequences. The HDAC6 and EZH2- binding peptides were then fused using linker sequences, and AlphaFold3 was employed to predict the resulting structures, thereby validating the feasibility of the fusion design and identifying high-confidence peptide candidates.</p><p><strong>Results: </strong>Through 100 ns molecular dynamics simulations, three peptide inhibitors were identified, and DTP-1 showed superior stability and binding free energies of －88.96 kcal/mol (HDAC6) and －62.53 kcal/mol (EZH2).</p><p><strong>Discussion: </strong>These findings substantiate the feasibility of an AI-guided workflow for designing dual-target peptide inhibitors that establish a foundation for enhancing the efficacy of epigenetic combination therapies and accelerating the development of dual-target inhibitors.</p><p><strong>Conclusion: </strong>This study introduces novel peptide inhibitors targeting HDAC6 and EZH2, along with a generalizable strategy for designing dual-target peptide inhibitors. DTP-1 emerges as a promising lead inhibitor for further preclinical development.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142969","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}