ACS Medicinal Chemistry Letters最新文献

Identification of Phosphodiesterase-7 Inhibitors with Spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1′-cyclohexan]-7-one Scaffold for the Treatment of Chronic Fatigue

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c0000110.1021/acsmedchemlett.5c00001

Zhendong Song, and , Steven H. Liang*,

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In This Issue, Volume 16, Issue 3

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c0008210.1021/acsmedchemlett.5c00082

Michelle A. Estrada,

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Identification of Phosphodiesterase-7 Inhibitors with Spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one Scaffold for the Treatment of Chronic Fatigue.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00001

Zhendong Song, Steven H Liang

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Correction to "Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria".

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-05 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00088

Longqin Hu, Akash Taneja, Husam Zahid, Yiling Wang, Min Yang, Zhihua An, Xingsheng Li, Jay A Tischfield, John Knight, Michael D Ward, Amrik Sahota

引用次数: 0

In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-04 DOI: 10.1021/acsmedchemlett.4c0063510.1021/acsmedchemlett.4c00635

Shu-Qin Wang, Xinyu Wang, Lingling Guo, Xiao-Xia Chen, Xiao-Jun Huang, Shiqing Zhang, Wen-Cai Ye, Xiao-Qi Zhang*, Lei Shi*, Ying Wang* and Li-Jun Hu*,

{"title":"In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity","authors":"Shu-Qin Wang, Xinyu Wang, Lingling Guo, Xiao-Xia Chen, Xiao-Jun Huang, Shiqing Zhang, Wen-Cai Ye, Xiao-Qi Zhang*, Lei Shi*, Ying Wang* and Li-Jun Hu*, ","doi":"10.1021/acsmedchemlett.4c0063510.1021/acsmedchemlett.4c00635","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00635https://doi.org/10.1021/acsmedchemlett.4c00635","url":null,"abstract":"Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer’s disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"475–482 475–482"},"PeriodicalIF":3.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600444","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

Correction to “Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria”

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-04 DOI: 10.1021/acsmedchemlett.5c0008810.1021/acsmedchemlett.5c00088

Longqin Hu*, Akash Taneja, Husam Zahid, Yiling Wang, Min Yang, Zhihua An, Xingsheng Li, Jay A. Tischfield, John Knight, Michael D. Ward and Amrik Sahota,

引用次数: 0

In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-03-04 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00635

Shu-Qin Wang, Xinyu Wang, Lingling Guo, Xiao-Xia Chen, Xiao-Jun Huang, Shiqing Zhang, Wen-Cai Ye, Xiao-Qi Zhang, Lei Shi, Ying Wang, Li-Jun Hu

{"title":"In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.","authors":"Shu-Qin Wang, Xinyu Wang, Lingling Guo, Xiao-Xia Chen, Xiao-Jun Huang, Shiqing Zhang, Wen-Cai Ye, Xiao-Qi Zhang, Lei Shi, Ying Wang, Li-Jun Hu","doi":"10.1021/acsmedchemlett.4c00635","DOIUrl":"10.1021/acsmedchemlett.4c00635","url":null,"abstract":"Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"475-482"},"PeriodicalIF":3.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655506","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

Morita–Baylis–Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-28 DOI: 10.1021/acsmedchemlett.4c0047910.1021/acsmedchemlett.4c00479

Marco Paolino*, Giusy Tassone, Paolo Governa, Mario Saletti, Matteo Lami, Riccardo Carletti, Filippo Sacchetta, Cecilia Pozzi, Maurizio Orlandini, Fabrizio Manetti, Massimo Olivucci and Andrea Cappelli,

{"title":"Morita–Baylis–Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands","authors":"Marco Paolino*, Giusy Tassone, Paolo Governa, Mario Saletti, Matteo Lami, Riccardo Carletti, Filippo Sacchetta, Cecilia Pozzi, Maurizio Orlandini, Fabrizio Manetti, Massimo Olivucci and Andrea Cappelli, ","doi":"10.1021/acsmedchemlett.4c0047910.1021/acsmedchemlett.4c00479","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00479https://doi.org/10.1021/acsmedchemlett.4c00479","url":null,"abstract":"The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs. It is driven by two fundamental steps: (1) recognition of the target site by the molecule and (2) establishment of the covalent interaction by its reactive group. The development of new TCIs depends on the development of new warheads. Here, we propose the use of Morita–Baylis–Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as a test bench for a library of 19 MBHAs. The noncovalent interaction step was investigated by molecular docking studies, while experimentally the entire library was incubated with M2 and crystallized to confirm covalent binding with the target lysine. The results, rationalized through covalent docking analysis, support our hypothesis of MBHAs as reactive scaffolds for the design of lysine-TCIs.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"397–405 397–405"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600364","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

Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-28 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00602

Abba E Leffler, Evelyne M Houang, Felicia Gray, Andrew T Placzek, Anatoly M Ruvinsky, Jeffrey A Bell, Hui Wang, Shaoxian Sun, Mats Svensson, Jeremy R Greenwood, Leah L Frye, Hideyuki Igawa, Christian Atsriku, Adam M Levinson

{"title":"Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.","authors":"Abba E Leffler, Evelyne M Houang, Felicia Gray, Andrew T Placzek, Anatoly M Ruvinsky, Jeffrey A Bell, Hui Wang, Shaoxian Sun, Mats Svensson, Jeremy R Greenwood, Leah L Frye, Hideyuki Igawa, Christian Atsriku, Adam M Levinson","doi":"10.1021/acsmedchemlett.4c00602","DOIUrl":"10.1021/acsmedchemlett.4c00602","url":null,"abstract":"Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906 and E909, constitute a potency handle that can improve inhibitor affinity by as much as 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure-Activity Relationship (SAR) and X-ray crystallographic studies demonstrate that this effect is attributable to the electrostatic interaction between the protein and ligand. This interaction could be repurposed to create new SOS1 inhibitors, documenting its general utility for core exploration. Additional recent examples in the literature suggest that this phenomenon may be applicable to a number of target classes and are highlighted herein.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"444-453"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655514","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

Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-28 DOI: 10.1021/acsmedchemlett.4c0060210.1021/acsmedchemlett.4c00602

Abba E. Leffler*, Evelyne M. Houang, Felicia Gray, Andrew T. Placzek, Anatoly M. Ruvinsky, Jeffrey A. Bell, Hui Wang, Shaoxian Sun, Mats Svensson, Jeremy R. Greenwood, Leah L. Frye, Hideyuki Igawa, Christian Atsriku and Adam M. Levinson*,

{"title":"Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations","authors":"Abba E. Leffler*, Evelyne M. Houang, Felicia Gray, Andrew T. Placzek, Anatoly M. Ruvinsky, Jeffrey A. Bell, Hui Wang, Shaoxian Sun, Mats Svensson, Jeremy R. Greenwood, Leah L. Frye, Hideyuki Igawa, Christian Atsriku and Adam M. Levinson*, ","doi":"10.1021/acsmedchemlett.4c0060210.1021/acsmedchemlett.4c00602","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00602https://doi.org/10.1021/acsmedchemlett.4c00602","url":null,"abstract":"Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906 and E909, constitute a potency handle that can improve inhibitor affinity by as much as 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure–Activity Relationship (SAR) and X-ray crystallographic studies demonstrate that this effect is attributable to the electrostatic interaction between the protein and ligand. This interaction could be repurposed to create new SOS1 inhibitors, documenting its general utility for core exploration. Additional recent examples in the literature suggest that this phenomenon may be applicable to a number of target classes and are highlighted herein.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"444–453 444–453"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600399","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