Archiv der Pharmazie最新文献_第8页

Sequential Optimization Approach Toward an Azapeptide-Based SARS-CoV-2 Main Protease Inhibitor 基于azapep肽的SARS-CoV-2主要蛋白酶抑制剂的序列优化研究

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-23 DOI: 10.1002/ardp.70175

Rabea Voget, Victoria Steiger, Julian Breidenbach, Katharina Sylvester, Christin Müller-Ruttloff, Chun-Chiao Yang, John Ziebuhr, Norbert Sträter, Christa E. Müller, Michael Gütschow

{"title":"Sequential Optimization Approach Toward an Azapeptide-Based SARS-CoV-2 Main Protease Inhibitor","authors":"Rabea Voget, Victoria Steiger, Julian Breidenbach, Katharina Sylvester, Christin Müller-Ruttloff, Chun-Chiao Yang, John Ziebuhr, Norbert Sträter, Christa E. Müller, Michael Gütschow","doi":"10.1002/ardp.70175","DOIUrl":"10.1002/ardp.70175","url":null,"abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19), is still circulating and posing a health threat to the global population. Its main protease (Mpro) constitutes an excellent target for the development of antivirals due to its indispensable role in the viral replication cycle. In this work, we employed a sequential approach to identify a potent azapeptide-based Mpro inhibitor. Starting from a series of small-molecule peptidomimetics, identical in their scaffold but equipped with different cysteine-reactive groups, we identified auspicious warheads. The combination of selected moieties with an optimized, previously described P1–P4 azapeptide structure resulted in a potent Mpro inactivator (12) with a kinac/Ki value of 78,900 M–1s–1. The chloracetohydrazide derivative 12 exhibited antiviral activity (EC50 = 0.47 µM), no cytotoxicity, and plasma stability. The molecular interaction of 12 with Mpro was elucidated by an X-ray crystal structure. A thioether linkage was generated through a nucleophilic substitution of chloride by the active-site thiolate, giving rise to irreversible inhibition.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protacs Targeting ERα in the Effective Management of Endocrinal Resistance Breast Cancer 靶向ERα的Protacs在内分泌抵抗性乳腺癌中的有效治疗。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-23 DOI: 10.1002/ardp.70176

Anupriya Singh, Roshni Khan, Noora Amana Erachampatt, Neha Bhatia, Vikramdeep Monga, Suresh Thareja

{"title":"Protacs Targeting ERα in the Effective Management of Endocrinal Resistance Breast Cancer","authors":"Anupriya Singh, Roshni Khan, Noora Amana Erachampatt, Neha Bhatia, Vikramdeep Monga, Suresh Thareja","doi":"10.1002/ardp.70176","DOIUrl":"10.1002/ardp.70176","url":null,"abstract":"<div>\u0000 \u0000 The estrogen receptor is a central mediator of estrogen-driven gene expression, influencing a wide array of physiological processes. Conventional endocrine therapies, including selective estrogen receptor modulators (SERMs) and degraders (SERDs), often face limitations due to acquired resistance and reduced efficacy in ERα-mutant cancers. Proteolysis-targeting chimeras (PROTACs) serve as a next-generation therapeutic strategy designed to selectively and efficiently degrade estrogen receptor alpha (ERα). The approval of elacestrant further expanded interest in developing novel ERα degraders, shifting the paradigm of drug discovery in this area. This review highlights the mechanism of action of PROTACs, structural and functional domains of ERα, design of PROTACs, and their application in targeting the ERα receptor. Special emphasis is also given on structure activity relationship (SAR) studies and strategies of designing PROTACs reported in the literature, along with in vitro and in vivo studies data. Collectively, these strategies provide valuable insights for designing effective PROTACs to overcome endocrine resistance and advance therapeutic options in ERα-positive breast cancers.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-Angle Bioactivity Cartography for Computational Screening and Mechanistic Analysis of AChE Inhibitors From Yellow Gastrodia elata 黄天麻乙酰胆碱酯酶抑制剂计算筛选及机制分析的多角度生物活性制图。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-21 DOI: 10.1002/ardp.70174

Ruijun Sun, Yuchi Zhang, Jingying Xu, Ming Chen, Chunming Liu, Xuanlin Liu, Yang Zhou, Rong Tsao, Yoichiro Ito, Sainan Li

{"title":"Multi-Angle Bioactivity Cartography for Computational Screening and Mechanistic Analysis of AChE Inhibitors From Yellow Gastrodia elata","authors":"Ruijun Sun, Yuchi Zhang, Jingying Xu, Ming Chen, Chunming Liu, Xuanlin Liu, Yang Zhou, Rong Tsao, Yoichiro Ito, Sainan Li","doi":"10.1002/ardp.70174","DOIUrl":"10.1002/ardp.70174","url":null,"abstract":"<div>\u0000 \u0000 Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products—particularly botanical sources like Yellow Gastrodia elata (YGE)—serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC50 values (0.0145 and 0.0148 mM). Molecular dynamics and network pharmacology analyses further revealed critical interactions between these compounds and key AD-related targets, including ACHE, BCHE, BACE1, and PTGS2. In summary, this work underscores the potential of YGE-sourced compounds, especially parishins A and G, as effective AChE inhibitors. The established integrative computational platform facilitates multi-dimensional bioactivity evaluation and enables hierarchical prioritization of candidate compounds, thereby offering a valuable framework for advancing natural product-derived therapeutics for AD.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unraveling the Anticancer Activity of Sunitinib Derivatives Through Modifications in Solvent-Exposed Regions: Synthesis, In Vitro Evaluation, and Computational Studies 通过溶剂暴露区域的修饰揭示舒尼替尼衍生物的抗癌活性：合成，体外评价和计算研究。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-20 DOI: 10.1002/ardp.70168

Robby Gus Mahardika, Ade Danova, Chanat Aonbangkhen, Jaruwan Chatwichien, Sutthida Wongsuwan, Warinthorn Chavasiri, Elvira Hermawati, Anita Alni

{"title":"Unraveling the Anticancer Activity of Sunitinib Derivatives Through Modifications in Solvent-Exposed Regions: Synthesis, In Vitro Evaluation, and Computational Studies","authors":"Robby Gus Mahardika, Ade Danova, Chanat Aonbangkhen, Jaruwan Chatwichien, Sutthida Wongsuwan, Warinthorn Chavasiri, Elvira Hermawati, Anita Alni","doi":"10.1002/ardp.70168","DOIUrl":"10.1002/ardp.70168","url":null,"abstract":"<div>\u0000 \u0000 This study modified the solvent-exposed region of sunitinib by replacing its diethylaminoethyl tail with linear and heterocyclic amines, guided by lipophilicity, steric, and electronic considerations to enhance the anticancer activity and selectivity. Sunitinib and its 20 derivatives, including 14 new compounds (4a, 4c, 4d, 4g–4i, 5a, 5b, 7a–7e, and 8) and 6 known compounds (4b, 4e–4f, 5c–5d, and 6), were successfully synthesized. The cytotoxic effects of sunitinib and its derivatives were evaluated against three human cancer cell lines (HeLa, SH-SY5Y, and HepG2) and one normal cell line (L929) using the MTT assay. Sunitinib exhibited the strongest cytotoxicity toward SH-SY5Y neuroblastoma cells, with an IC₅₀ of 3.88 µM. Among the derivatives, compound 5b showed the highest potency with an IC₅₀ of 4.28 µM against SH-SY5Y. Compound 6 displayed the highest selectivity index (SI ≥ 5) for HeLa, indicating good selectivity toward cancer over normal cells. Overall, these results suggest that targeted modification of the solvent-exposed region in sunitinib can improve anticancer activity without toxicity against normal cell lines, with compound 5b emerging as a promising lead for further development, particularly against neuroblastoma. The solvent-exposed region is strategic for drug development, allowing modifications that improve affinity, selectivity, solubility, and pharmacokinetics without disrupting ligand-protein interactions.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quinoline/Pyrido-Pyrimidine Derivatives as Tubulin Polymerization Inhibitors: Design, Synthesis, Computational, and Anticancer Evaluation 喹啉/吡啶嘧啶衍生物作为微管蛋白聚合抑制剂：设计、合成、计算和抗癌评价。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-20 DOI: 10.1002/ardp.70172

Divyakshi Arya, Gulshan Aara Khan, Shweta Singh, Anjali Upadhyay, Bharat Prasad Sharma, Rajesh Maharjan, Motee Lal Sharma, Munna P. Gupt, Som Shankar Dubey, Prateek Pathak, Ashish Ranjan Dwivedi, Sarvesh Kumar Pandey

{"title":"Quinoline/Pyrido-Pyrimidine Derivatives as Tubulin Polymerization Inhibitors: Design, Synthesis, Computational, and Anticancer Evaluation","authors":"Divyakshi Arya, Gulshan Aara Khan, Shweta Singh, Anjali Upadhyay, Bharat Prasad Sharma, Rajesh Maharjan, Motee Lal Sharma, Munna P. Gupt, Som Shankar Dubey, Prateek Pathak, Ashish Ranjan Dwivedi, Sarvesh Kumar Pandey","doi":"10.1002/ardp.70172","DOIUrl":"10.1002/ardp.70172","url":null,"abstract":"<div>\u0000 \u0000 Cancer prevails a substantial health threat, with breast and colon cancers being the second and third most recurrent worldwide. In recent decades, quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives have procured attention as propitious anticancer agents. This study acquaint a series of such compounds synthesized and characterized using spectroscopic (1H NMR, 13C NMR, IR, MS) and computational (DFT) methods. Their tubulin polymerization inhibitory and antiproliferative activities were assessed against cancer cell lines MCF-7, MDA-MB-231, and HCT-116, accompanying cytotoxicity screening against normal HEK-293 cells, divulging selective anticancer potential. SAR study accentuated the role of methoxy-substituted phenyl and cycloheptane rings in escalating activity. Peculiarly, compound 4g (IC50 = 3.02 ± 0.63 μM against cell line MCF-7) exhibited profound tubulin inhibition and was additionally substantiated via molecular docking and dynamics simulations, ratifying its drug-like behavior.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Integrated In Silico–In Vitro Evaluation of Triazole-Linked Benz/Imidazole-2-Thione/Selone Derivatives as Selective CDK1 Inhibitors for Breast Cancer Therapy 设计，合成和集成在硅-体外评价三唑连接的奔驰/咪唑-2-硫酮/Selone衍生物作为选择性CDK1抑制剂用于乳腺癌治疗。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-19 DOI: 10.1002/ardp.70173

Alameer Ezat Abdulkareem, Ahmed Hassoon Mageed

{"title":"Design, Synthesis, and Integrated In Silico–In Vitro Evaluation of Triazole-Linked Benz/Imidazole-2-Thione/Selone Derivatives as Selective CDK1 Inhibitors for Breast Cancer Therapy","authors":"Alameer Ezat Abdulkareem, Ahmed Hassoon Mageed","doi":"10.1002/ardp.70173","DOIUrl":"10.1002/ardp.70173","url":null,"abstract":"<div>\u0000 \u0000 Benz/imidazole-2-thione/selone-based triazoles, particularly their thione and selone analogs, are gaining attention for anticancer drug development due to their structural diversity and biological activity. However, their potential as targeted inhibitors of cancer-related proteins remains underexplored. This study reports the design, synthesis, and evaluation of novel benz/imidazole-2-thione/selone-based triazoles, focusing on cyclin-dependent kinase 1 (CDK1), a key regulator of cancer cell proliferation. The compounds were synthesized via a multistep approach involving imidazolium salt intermediates, followed by sulfur or selenium incorporation. Structural confirmation was achieved using FT-IR, NMR, and mass spectrometry. Molecular docking against CDK1, TERT, and VEGFR2 revealed strong binding affinities (−9.7 to −7.3 kcal/mol), with CDK1 selected for further in vitro study using MCF-7 breast cancer cells. Molecular dynamics (MD) simulations confirmed stable CDK1 binding for Compounds 2, 4, and 9, although Compound 9 showed conformational instability after 60 ns. ADMET profiling indicated favorable drug-likeness and permeability but highlighted metabolic liabilities and hERG inhibition risks, particularly for Compounds 4 and 9. The target prediction and pathway enrichment analyses predict that benz/imidazole-2-thione/selone-based triazoles exert their pharmacological effects primarily through the regulation of GPCR signaling pathways, likely via direct interaction with key regulators such as RGS8 and RGS4. In vitro assays demonstrated dose-dependent cytotoxicity, with Compound 4 showing the highest potency (IC50 = 106.12 ± 1.03 µg/mL), followed by 9 and 2. These findings suggest that benz/imidazole-2-thione/selone-based triazoles are promising CDK1 inhibitors and support their further optimization as targeted breast cancer therapies.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Biological Evaluation of Novel Benzimidazole/Schiff Base Hybrid Derivatives With Potential Biological Activities 具有潜在生物活性的新型苯并咪唑/希夫碱杂化衍生物的设计、合成及生物学评价。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-15 DOI: 10.1002/ardp.70165

Mohamed Y. Abdel-Hady, Martha M. Morcoss, Abdullah Yahya Abdullah Alzahrani, Bahaa G. M. Youssif, El Shimaa M. N. Abdelhafez, Mohamed Abdel-Aziz

{"title":"Design, Synthesis, and Biological Evaluation of Novel Benzimidazole/Schiff Base Hybrid Derivatives With Potential Biological Activities","authors":"Mohamed Y. Abdel-Hady, Martha M. Morcoss, Abdullah Yahya Abdullah Alzahrani, Bahaa G. M. Youssif, El Shimaa M. N. Abdelhafez, Mohamed Abdel-Aziz","doi":"10.1002/ardp.70165","DOIUrl":"10.1002/ardp.70165","url":null,"abstract":"<div>\u0000 \u0000 A novel series of benzimidazole-based derivatives (5a–g), (6a–b), and (7a–b) were designed, synthesized, and evaluated for their potential as dual inhibitors of EGFR and HER-2. The synthesized compounds were subjected to in vitro screening against a panel of selected human cancer cell lines. Additionally, their cytotoxicity was assessed using normal human mammary epithelial cells (MCF-10A) to evaluate their safety profile. Among the tested derivatives, compounds 5b, 5f, and 6a demonstrated the most pronounced antiproliferative activity, exhibiting IC₅₀ values of 6, 8, and 5 µM, respectively. These values reflect a potency at least fourfold greater than that of the reference drug Doxorubicin (IC₅₀ = 33 µM). EGFR and HER-2 enzyme inhibition assays were conducted to explore the potential molecular targets responsible for the observed anticancer effects. Notably, compound 6a (R₁ = phenyl, thiosemicarbazide) exhibited superior efficacy against the MCF-7 breast cancer cell line, with an IC₅₀ of 5 µM, approximately six times more potent than Doxorubicin. Conversely, compound 7b, with an IC₅₀ value of 85 µM against MCF-7 cells, was the least active, underscoring the critical role of the phenyl moiety in antiproliferative activity. Furthermore, a molecular docking study was conducted to investigate the binding interactions of 6a within the active sites of EGFR and HER-2, providing insight into its potential mechanism of action.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alantolactone as a Bioactive Sesquiterpene Lactone: Molecular Mechanisms and Anticancer Potential for Pharmaceutical Development Alantolactone是一种具有生物活性的倍半萜内酯：分子机制和药物开发的抗癌潜力。

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-14 DOI: 10.1002/ardp.70170

Alice Njolke Mafe, Lipana Dorcas Bappa, Javad Sharifi-Rad, William N. Setzer, Daniela Calina

{"title":"Alantolactone as a Bioactive Sesquiterpene Lactone: Molecular Mechanisms and Anticancer Potential for Pharmaceutical Development","authors":"Alice Njolke Mafe, Lipana Dorcas Bappa, Javad Sharifi-Rad, William N. Setzer, Daniela Calina","doi":"10.1002/ardp.70170","DOIUrl":"10.1002/ardp.70170","url":null,"abstract":"<div>\u0000 \u0000 Cancer remains a major global health challenge, responsible for millions of deaths each year. The limitations of current therapies, including adverse effects and drug resistance, have intensified the search for safer, more effective alternatives, particularly from natural sources. Alantolactone, a sesquiterpene lactone extracted from Inula helenium and related medicinal plants, has emerged as a promising anticancer candidate due to its diverse pharmacological actions. Although notable anticancer properties have been reported, its full therapeutic potential, mechanisms of action, and translational relevance remain insufficiently explored and scattered across the literature. This review provides a comprehensive synthesis of current evidence on alantolactone's anticancer effects. It examines its sources, phytochemical features, structure–activity relationships, bioavailability challenges, mechanistic pathways, and preclinical findings, alongside perspectives for future clinical application. Evidence shows that alantolactone modulates multiple molecular targets and signaling cascades, including NF-κB, STAT3, MAPK, and apoptotic regulators. It demonstrates strong cytotoxic activity across diverse cancer cell lines and tumor-bearing animal models. However, barriers such as low systemic bioavailability, limited pharmacokinetic profiling, and the absence of human clinical data impede its therapeutic development. Alantolactone nonetheless holds significant promise as a multi-targeted anticancer compound with encouraging preclinical outcomes. Further research is required to address pharmacological limitations and establish safety and efficacy in clinical contexts. This review highlights alantolactone's potential contribution to future cancer therapy and emphasizes the need for interdisciplinary research to support its clinical translation and formulation advancement.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Support Vector Machine Identification of Small Molecule Binders to an Understudied Allosteric Site of SARS-CoV-2 Mpro for Next-Generation PROTAC-Based Therapeutics 支持向量机识别新一代基于protac的治疗方法中尚未研究的SARS-CoV-2 Mpro变弹性位点的小分子结合物

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-13 DOI: 10.1002/ardp.70169

Enrico Mario Alessandro Fassi, Nedra Mekni, Marco Albani, Sabine Maehrlein, Annabelle Carolin Weldert, Tanja Schirmeister, Thierry Langer, Giovannf razioso

{"title":"Support Vector Machine Identification of Small Molecule Binders to an Understudied Allosteric Site of SARS-CoV-2 Mpro for Next-Generation PROTAC-Based Therapeutics","authors":"Enrico Mario Alessandro Fassi, Nedra Mekni, Marco Albani, Sabine Maehrlein, Annabelle Carolin Weldert, Tanja Schirmeister, Thierry Langer, Giovannf razioso","doi":"10.1002/ardp.70169","DOIUrl":"10.1002/ardp.70169","url":null,"abstract":"The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the urgent need for novel antiviral strategies. One of the primary targets of interest is the SARS-CoV-2 main protease (Mpro), which plays a crucial role in viral replication. Building on our prior work involving machine learning (ML)-based virtual screening for potential Mpro inhibitors, we sought to experimentally validate top-ranked candidates. Microscale thermophoresis (MST) was used to assess the binding affinity, leading to the identification of three promising hits from a library of 180 compounds. Notably, one compound demonstrated high-affinity binding to SARS-CoV-2 Mpro (Kd = 2.8 ± 0.9 µM). However, enzymatic assays revealed that none of the hit compounds inhibited the activity of the protease, suggesting a non-competitive binding. Docking and molecular dynamics (MD) simulations allowed to identify an accessory site in which the compounds exhibited stable interactions. These findings suggest that the identified compounds may serve as a starting point for the rational design of degradation-inducing strategies, such as proteolysis-targeting chimeras (PROTACs), targeting SARS-CoV-2 Mpro, and highlight the value of integrating ML-driven discovery with biophysical and computational validation in antiviral drug development.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Uro-Protective Role of Lacosamide Against Cyclophosphamide-Induced Cystitis via Notch1/NICD/NF-κB Pathway: Network Pharmacology, Molecular Docking, and Rat Model Validation 拉科沙胺通过Notch1/NICD/NF-κB通路对环磷酰胺性膀胱炎的尿保护作用：网络药理学、分子对接及大鼠模型验证

IF 3.6 3区医学

Archiv der Pharmazie Pub Date : 2025-12-13 DOI: 10.1002/ardp.70171

Ahmed S. Abdel-Samea, Mohammed R. A. Ali, Reham H. Mohyeldin, Mina Ezzat Attya, Basim A. S. Messiha

{"title":"Uro-Protective Role of Lacosamide Against Cyclophosphamide-Induced Cystitis via Notch1/NICD/NF-κB Pathway: Network Pharmacology, Molecular Docking, and Rat Model Validation","authors":"Ahmed S. Abdel-Samea, Mohammed R. A. Ali, Reham H. Mohyeldin, Mina Ezzat Attya, Basim A. S. Messiha","doi":"10.1002/ardp.70171","DOIUrl":"10.1002/ardp.70171","url":null,"abstract":"<div>\u0000 \u0000 Cystitis, characterized by bladder inflammation, represents a significant clinical challenge in cancer chemotherapy, particularly with cyclophosphamide administration. Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers increased efficiency, reduced costs, and lower risks. This study investigated the molecular mechanisms underlying the uro-protective application of lacosamide, an FDA-approved antiepileptic drug, against cyclophosphamide-induced cystitis via suppression of the Notch-1/NICD/NF-κB inflammatory pathway. Network pharmacology analysis identified key molecular targets and pathways involved in lacosamide's protective mechanisms, followed by molecular docking studies that validated the binding interactions between lacosamide and target proteins. In vivo validation was performed using adult male Wistar rats with cyclophosphamide-induced cystitis. Network analysis revealed Notch-1 as a primary target for lacosamide's uroprotective action. Experimental validation demonstrated that lacosamide pretreatment significantly attenuated oxidative bladder injury by decreasing malondialdehyde levels while enhancing superoxide dismutase activity and reduced glutathione content. Lacosamide substantially downregulated pro-inflammatory mediators including TNF-α, IL-1β, and IL-6 via NF-κB suppression. Additionally, lacosamide suppressed the Notch-1/NICD/NF-κB pathway, elevated Bcl-2 expression, and reduced Bax protein and caspase-3 levels. Histopathological examination corroborated biochemical findings. Lacosamide demonstrates significant uro-protective efficacy through coordinated anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through modulation of Notch-1/NICD/NF-κB pathway.</div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0