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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 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c0000110.1021/acsmedchemlett.5c00001
Zhendong Song,  and , Steven H. Liang*, 

The invention in this patent relates to the use of phosphodiesterase-7 (PDE7) inhibitors with a spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1′-cyclohexan]-7-one scaffold for the treatment and prevention of diseases and syndromes associated with chronic fatigue, exhaustion, and exertional intolerance.

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引用次数: 0
In This Issue, Volume 16, Issue 3
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c0008210.1021/acsmedchemlett.5c00082
Michelle A. Estrada, 
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引用次数: 0
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 Q2 CHEMISTRY, MEDICINAL Pub Date : 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00001
Zhendong Song, Steven H Liang

The invention in this patent relates to the use of phosphodiesterase-7 (PDE7) inhibitors with a spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one scaffold for the treatment and prevention of diseases and syndromes associated with chronic fatigue, exhaustion, and exertional intolerance.

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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 Q2 CHEMISTRY, MEDICINAL 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

[This corrects the article DOI: 10.1021/acsmedchemlett.4c00423.].

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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 Q2 CHEMISTRY, MEDICINAL 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*, 

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.

{"title":"In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity","authors":"Shu-Qin Wang,&nbsp;Xinyu Wang,&nbsp;Lingling Guo,&nbsp;Xiao-Xia Chen,&nbsp;Xiao-Jun Huang,&nbsp;Shiqing Zhang,&nbsp;Wen-Cai Ye,&nbsp;Xiao-Qi Zhang*,&nbsp;Lei Shi*,&nbsp;Ying Wang* and Li-Jun Hu*,&nbsp;","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":"<p >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 <i>in-vitro</i> evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds <b>17</b> and <b>23</b> potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that <b>17</b> and <b>23</b> may stably bind to the eEF2K protein. Our findings highlighted <b>17</b> and <b>23</b> as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.</p>","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 Q2 CHEMISTRY, MEDICINAL 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, 
{"title":"Correction to “Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria”","authors":"Longqin Hu*,&nbsp;Akash Taneja,&nbsp;Husam Zahid,&nbsp;Yiling Wang,&nbsp;Min Yang,&nbsp;Zhihua An,&nbsp;Xingsheng Li,&nbsp;Jay A. Tischfield,&nbsp;John Knight,&nbsp;Michael D. Ward and Amrik Sahota,&nbsp;","doi":"10.1021/acsmedchemlett.5c0008810.1021/acsmedchemlett.5c00088","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00088https://doi.org/10.1021/acsmedchemlett.5c00088","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"496 496"},"PeriodicalIF":3.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600445","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
In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL 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

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.

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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 Q2 CHEMISTRY, MEDICINAL 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, 

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.

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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 Q2 CHEMISTRY, MEDICINAL 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

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.

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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 Q2 CHEMISTRY, MEDICINAL 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*, 

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.

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引用次数: 0
期刊
ACS Medicinal Chemistry Letters
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