ACS Medicinal Chemistry Letters最新文献_第8页

Many Faces: The Global Landscape of Medicinal Chemistry

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-12 DOI: 10.1021/acsmedchemlett.5c0004110.1021/acsmedchemlett.5c00041

Lori Ferrins*, Ashley Adams and Anna Junker*,

引用次数: 0

Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-11 DOI: 10.1021/acsmedchemlett.5c0006610.1021/acsmedchemlett.5c00066

Ram W. Sabnis*, and , Anika R. Sabnis,

引用次数: 0

Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-11 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00066

Ram W Sabnis, Anika R Sabnis

引用次数: 0

Structural Studies of the Dopamine D₄ Receptor Antagonist Sonepiprazole as an Inhibitor of Human Carbonic Anhydrases.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00034

Andrea Angeli, Marta Ferraroni, Clemente Capasso, Claudiu T Supuran

{"title":"Structural Studies of the Dopamine D4 Receptor Antagonist Sonepiprazole as an Inhibitor of Human Carbonic Anhydrases.","authors":"Andrea Angeli, Marta Ferraroni, Clemente Capasso, Claudiu T Supuran","doi":"10.1021/acsmedchemlett.5c00034","DOIUrl":"10.1021/acsmedchemlett.5c00034","url":null,"abstract":"In this study, we provide the first evidence that sonepiprazole, a dopamine D4 receptor antagonist, acts as a potent inhibitor of human carbonic anhydrases (hCAs). Sonepiprazole exhibited significant inhibitory activity across the panel of catalytically active hCAs, with the exception of hCA IV, and hCA III. The most potent inhibition was observed against the brain-associated isoform hCA VII, with a K I of 2.9 nM. Insights from X-ray crystallographic structures of the complexes with hCA I, hCA II, and hCA XII revealed that the sulfonamide group of sonepiprazole coordinates the zinc ion in the active site, a typical interaction for this class of inhibitors. Despite the presence of isoform-specific residues at the rim of the active site pocket, these variations seem not to significantly impact the compound overall inhibition potency. These findings highlight a dual functionality of sonepiprazole as both a D4 receptor antagonist and a carbonic anhydrase inhibitor.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"483-486"},"PeriodicalIF":3.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655580","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

Structural Studies of the Dopamine D4 Receptor Antagonist Sonepiprazole as an Inhibitor of Human Carbonic Anhydrases

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 DOI: 10.1021/acsmedchemlett.5c0003410.1021/acsmedchemlett.5c00034

Andrea Angeli*, Marta Ferraroni, Clemente Capasso and Claudiu T. Supuran,

{"title":"Structural Studies of the Dopamine D4 Receptor Antagonist Sonepiprazole as an Inhibitor of Human Carbonic Anhydrases","authors":"Andrea Angeli*, Marta Ferraroni, Clemente Capasso and Claudiu T. Supuran, ","doi":"10.1021/acsmedchemlett.5c0003410.1021/acsmedchemlett.5c00034","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00034https://doi.org/10.1021/acsmedchemlett.5c00034","url":null,"abstract":"In this study, we provide the first evidence that sonepiprazole, a dopamine D4 receptor antagonist, acts as a potent inhibitor of human carbonic anhydrases (hCAs). Sonepiprazole exhibited significant inhibitory activity across the panel of catalytically active hCAs, with the exception of hCA IV, and hCA III. The most potent inhibition was observed against the brain-associated isoform hCA VII, with a KI of 2.9 nM. Insights from X-ray crystallographic structures of the complexes with hCA I, hCA II, and hCA XII revealed that the sulfonamide group of sonepiprazole coordinates the zinc ion in the active site, a typical interaction for this class of inhibitors. Despite the presence of isoform-specific residues at the rim of the active site pocket, these variations seem not to significantly impact the compound overall inhibition potency. These findings highlight a dual functionality of sonepiprazole as both a D4 receptor antagonist and a carbonic anhydrase inhibitor.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"483–486 483–486"},"PeriodicalIF":3.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600231","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

A Hybrid Energy-Based and AI-Based Screening Approach for the Discovery of Novel Inhibitors of AXL.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00511

Xinting Lv, Youkun Kang, Xinglong Chi, Jingyi Zhao, Zhichao Pan, Xiaojun Ying, Long Li, Youlu Pan, Wenhai Huang, Linjun Wang

引用次数: 0

Enhanced Cytotoxicity of [10]-Gingerol-Coumarin-Triazole Hybrid as a Theranostic Agent for Triple Negative Breast Cancer.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00596

Arthur Deponte Zutião, Bianca Cruz Pachane, Paulo Sérgio Gonçalves Nunes, Herika Danielle Almeida Vidal, Heloisa Sobreiro Selistre-de-Araujo, Arlene Gonçalves Corrêa, Marcia Regina Cominetti, Angelina Maria Fuzer

{"title":"Enhanced Cytotoxicity of [10]-Gingerol-Coumarin-Triazole Hybrid as a Theranostic Agent for Triple Negative Breast Cancer.","authors":"Arthur Deponte Zutião, Bianca Cruz Pachane, Paulo Sérgio Gonçalves Nunes, Herika Danielle Almeida Vidal, Heloisa Sobreiro Selistre-de-Araujo, Arlene Gonçalves Corrêa, Marcia Regina Cominetti, Angelina Maria Fuzer","doi":"10.1021/acsmedchemlett.4c00596","DOIUrl":"10.1021/acsmedchemlett.4c00596","url":null,"abstract":"A leading cause of death worldwide, breast cancer is the second most prevalent cancer in women. Triple-negative breast cancer is an aggressive subtype that lacks targeted therapies and requires novel therapeutic approaches in clinical practice to improve the overall survival. Theranostic agents that integrate diagnostic and therapeutic capabilities in a single entity are promising strategies for personalized cancer management. Hybrid compounds combining biologically relevant moieties with different modes of action can enhance cytotoxicity and improve pharmacological properties. We focus on a hybrid containing coumarin, triazole, and [10]-gingerol, a compound with known antimetastatic potential in TNBC. The LSPN281 hybrid exhibited superior cytotoxic activity in a TNBC cell line in vitro compared to the individual coumarin and [10]-gingerol controls. Additionally, the hybrid shows enhanced cellular uptake and mitochondrial localization, suggesting its potential as a theranostic agent for TNBC.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"436-443"},"PeriodicalIF":3.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655513","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

A Hybrid Energy-Based and AI-Based Screening Approach for the Discovery of Novel Inhibitors of AXL

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-10 DOI: 10.1021/acsmedchemlett.4c0051110.1021/acsmedchemlett.4c00511

Xinting Lv, Youkun Kang, Xinglong Chi, Jingyi Zhao, Zhichao Pan, Xiaojun Ying, Long Li, Youlu Pan, Wenhai Huang* and Linjun Wang*,

{"title":"A Hybrid Energy-Based and AI-Based Screening Approach for the Discovery of Novel Inhibitors of AXL","authors":"Xinting Lv, Youkun Kang, Xinglong Chi, Jingyi Zhao, Zhichao Pan, Xiaojun Ying, Long Li, Youlu Pan, Wenhai Huang* and Linjun Wang*, ","doi":"10.1021/acsmedchemlett.4c0051110.1021/acsmedchemlett.4c00511","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00511https://doi.org/10.1021/acsmedchemlett.4c00511","url":null,"abstract":"AXL, part of the TAM receptor tyrosine kinase family, plays a significant role in the growth and survival of various tissues and tumors, making it a critical target for cancer therapy. This study introduces a novel high-throughput virtual screening (HTVS) methodology that merges an AI-enhanced graph neural network, PLANET, with a geometric deep learning algorithm, DeepDock. Using this approach, we identified potent AXL inhibitors from our database. Notably, compound 9, with an IC50 of 9.378 nM, showed excellent inhibitory activity, suggesting its potential as a candidate for further research. We also performed molecular dynamics simulations to explore the interactions between compound 9 and AXL, providing insights for future enhancements. This hybrid screening method proves effective in finding promising AXL inhibitors, and advancing the development of new cancer therapies.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"410–419 410–419"},"PeriodicalIF":3.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600232","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

Enhanced Cytotoxicity of [10]-Gingerol-Coumarin-Triazole Hybrid as a Theranostic Agent for Triple Negative Breast Cancer 增强[10]-姜酚-香豆素-三唑混合物作为三阴性乳腺癌抗肿瘤药物的细胞毒性

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-09 DOI: 10.1021/acsmedchemlett.4c0059610.1021/acsmedchemlett.4c00596

Arthur Deponte Zutião, Bianca Cruz Pachane, Paulo Sérgio Gonçalves Nunes, Herika Danielle Almeida Vidal, Heloisa Sobreiro Selistre-de-Araujo, Arlene Gonçalves Corrêa, Marcia Regina Cominetti and Angelina Maria Fuzer*,

{"title":"Enhanced Cytotoxicity of [10]-Gingerol-Coumarin-Triazole Hybrid as a Theranostic Agent for Triple Negative Breast Cancer","authors":"Arthur Deponte Zutião, Bianca Cruz Pachane, Paulo Sérgio Gonçalves Nunes, Herika Danielle Almeida Vidal, Heloisa Sobreiro Selistre-de-Araujo, Arlene Gonçalves Corrêa, Marcia Regina Cominetti and Angelina Maria Fuzer*, ","doi":"10.1021/acsmedchemlett.4c0059610.1021/acsmedchemlett.4c00596","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00596https://doi.org/10.1021/acsmedchemlett.4c00596","url":null,"abstract":"A leading cause of death worldwide, breast cancer is the second most prevalent cancer in women. Triple-negative breast cancer is an aggressive subtype that lacks targeted therapies and requires novel therapeutic approaches in clinical practice to improve the overall survival. Theranostic agents that integrate diagnostic and therapeutic capabilities in a single entity are promising strategies for personalized cancer management. Hybrid compounds combining biologically relevant moieties with different modes of action can enhance cytotoxicity and improve pharmacological properties. We focus on a hybrid containing coumarin, triazole, and [10]-gingerol, a compound with known antimetastatic potential in TNBC. The LSPN281 hybrid exhibited superior cytotoxic activity in a TNBC cell line in vitro compared to the individual coumarin and [10]-gingerol controls. Additionally, the hybrid shows enhanced cellular uptake and mitochondrial localization, suggesting its potential as a theranostic agent for TNBC.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"436–443 436–443"},"PeriodicalIF":3.5,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600432","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

Quantum Mechanics-Based Ranking of Predicted Proteolysis Targeting Chimeras-Mediated Ternary Complexes 基于量子力学的以嵌合体为目标的三元复合物蛋白质分解预测排名

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-06 DOI: 10.1021/acsmedchemlett.4c0053410.1021/acsmedchemlett.4c00534

Stefania Monteleone, Inaki Morao*, Dmitri G. Fedorov and Tahsin F. Kellici,

{"title":"Quantum Mechanics-Based Ranking of Predicted Proteolysis Targeting Chimeras-Mediated Ternary Complexes","authors":"Stefania Monteleone, Inaki Morao*, Dmitri G. Fedorov and Tahsin F. Kellici, ","doi":"10.1021/acsmedchemlett.4c0053410.1021/acsmedchemlett.4c00534","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00534https://doi.org/10.1021/acsmedchemlett.4c00534","url":null,"abstract":"Targeted protein degradation has become the most pursued alternative modality to small-molecule inhibition over the past decade. The traditional strategy of blocking protein activity by tightly binding to a functional substrate pocket has progressed toward proteolysis-targeting chimeras (PROTACs), bivalent molecules that induce the knockdown of targeted proteins. Herein, a combined protocol is described for modeling ternary complexes via well-established approaches. We performed local protein–protein docking using Rosetta protocol and sampled the conformational landscape of a specific PROTAC molecule that was compatible with the generated protein–protein docking poses, followed by double and independent single-linkage/nearest-neighbor clustering for representative selection. Subsequently, we combined the fragment molecular orbital and density functional tight-binding methods to facilitate fast quantum mechanics-based energy calculations of the clustered ternary complexes. Finally, the computed energy values were utilized to score and select the best ternary poses, achieving good agreement with available crystallographic data.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"420–427 420–427"},"PeriodicalIF":3.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600431","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