Pub Date : 2024-12-28DOI: 10.1016/j.ejmech.2024.117227
Telukuntla Sai Priya, Poonam Patil, Bandi Siva, Diya Roy, Radhika Dhote, Deepti Parashar, Kalichamy Alagarasu, Sarah Cherian, K. Suresh Babu
Investigations into fruit and vegetable processing residues (FVPRs) offer huge opportunities to discover novel therapeutics against many diseases. In this study, detailed investigation of Garcinia mangostana fruit peel extract led to the isolation and identification of ten known compounds (1-10). Further, a new series of α-mangostin derived sulphonamides, aryl alkynes and 1,2,3-triazole derivatives were synthesized using Huisgen 1,3-dipolar cyclo-addition reaction (“click” chemistry). Both isolated compounds and synthetic derivatives were evaluated for their anti-chikungunya activity (CHIKV). Isolated compounds, gartanin (1), mangostenone-F (4), 1-isomangostin (5), mangostenone-D (6), epicatechin (7) and derivatives 14, 15c, 15d, 15e, 15f, 17d, 17f, and 18h exerted anti-CHIKV activity. Compounds 17d, 17f and 18h manifested higher antiviral activity (>2 log reduction in virus titer) with a selectivity index (SI) > 50. The compounds with higher antiviral activity were evaluated further with various assays, time of addition assay, entry and entry bypass assay and were also subjected to molecular docking with viral proteins. The results revealed that 17d, 17f and 18h affect multiple stages of virus life cycle through probable interaction with envelope proteins and nsP3 macrodomain of CHIKV. Overall, this study provides evidence for anti CHIKV activity of natural xanthones from Garcinia mangostana L and their derivatives which could be further investigated for development of therapeutics against chikungunya.
{"title":"Novel α-mangostin Derivatives as Promising Antiviral Agents: Isolation, Synthesis, and Evaluation Against Chikungunya Virus","authors":"Telukuntla Sai Priya, Poonam Patil, Bandi Siva, Diya Roy, Radhika Dhote, Deepti Parashar, Kalichamy Alagarasu, Sarah Cherian, K. Suresh Babu","doi":"10.1016/j.ejmech.2024.117227","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117227","url":null,"abstract":"Investigations into fruit and vegetable processing residues (FVPRs) offer huge opportunities to discover novel therapeutics against many diseases. In this study, detailed investigation of <em>Garcinia mangostana</em> fruit peel extract led to the isolation and identification of ten known compounds (<strong>1</strong>-<strong>10</strong>). Further, a new series of α-mangostin derived sulphonamides, aryl alkynes and 1,2,3-triazole derivatives were synthesized using Huisgen 1,3-dipolar cyclo-addition reaction (“click” chemistry). Both isolated compounds and synthetic derivatives were evaluated for their anti-chikungunya activity (CHIKV). Isolated compounds, gartanin (<strong>1</strong>), mangostenone-F (<strong>4</strong>), 1-isomangostin (<strong>5</strong>), mangostenone-D (<strong>6</strong>), epicatechin (<strong>7</strong>) and derivatives <strong>14</strong>, <strong>15c</strong>, <strong>15d, 15e, 15f, 17d, 17f,</strong> and <strong>18h</strong> exerted anti-CHIKV activity. Compounds <strong>17d</strong>, <strong>17f</strong> and <strong>18h</strong> manifested higher antiviral activity (>2 log reduction in virus titer) with a selectivity index (SI) > 50. The compounds with higher antiviral activity were evaluated further with various assays, time of addition assay, entry and entry bypass assay and were also subjected to molecular docking with viral proteins. The results revealed that <strong>17d</strong>, <strong>17f</strong> and <strong>18h</strong> affect multiple stages of virus life cycle through probable interaction with envelope proteins and nsP3 macrodomain of CHIKV. Overall, this study provides evidence for anti CHIKV activity of natural xanthones from <em>Garcinia mangostana</em> L and their derivatives which could be further investigated for development of therapeutics against chikungunya.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.ejmech.2024.117214
Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade
Four photosensitizers PS1a-PS4a consisting in multicationic Ruthenium(II) Phthalocyanines (RuPcs) have been evaluated in photodynamic inactivation (PDI) of multiresistant microorganisms. The RuPcs, bearing from 4 to 12 terminal ammonium salts, have been designed to target the microorganisms cytoplasmic cell membrane and display high singlet oxygen quantum yields. In addition, PS3a and PS4a were conceived to exhibit multi-target localization by endowing them with amphiphilic character, using two different structural approaches. Under low light regimes, the two hydrophilic PS1a and PS2a, as well as the amphiphilic PS3a show much stronger response against gram-positive MRSA than that observed for the typical phthalocyanines designed for PDI, namely zinc(II) and palladium(II) complexes, as well as free-base Pcs. Besides, PS1a, PS2a and PS3a show remarkably high activity against the gram-negative E. coli, although weak fungicidal character against fluconazole-resistant C. albicans. Contrasting, the structurally different, amphiphilic PS4a shows only slight activity for Gram-positive bacteria, despite its ability to cross cell membrane and reach internal organelles. Still, PS4a shows a positive synergistic effect against MRSA when combined with doxycycline, exhibiting an increased activity from about 1.5 to about 4.9 log reduction under the light dose of 30 J/cm2 and the 0.125 mg/L subinhibitory dose of doxycycline.
{"title":"Multicationic Ruthenium Phthalocyanines as Photosensitizers for Photodynamic Inactivation of Multiresistant Microbes","authors":"Ana Belén Domínguez, Daniel Ziental, Jolanta Długaszewska, Lukasz Sobotta, Tomás Torres, M. Salomé Rodríguez-Morgade","doi":"10.1016/j.ejmech.2024.117214","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117214","url":null,"abstract":"Four photosensitizers <strong>PS1a-PS4a</strong> consisting in multicationic Ruthenium(II) Phthalocyanines (RuPcs) have been evaluated in photodynamic inactivation (PDI) of multiresistant microorganisms. The RuPcs, bearing from 4 to 12 terminal ammonium salts, have been designed to target the microorganisms cytoplasmic cell membrane and display high singlet oxygen quantum yields. In addition, <strong>PS3a</strong> and <strong>PS4a</strong> were conceived to exhibit multi-target localization by endowing them with amphiphilic character, using two different structural approaches. Under low light regimes, the two hydrophilic <strong>PS1a</strong> and <strong>PS2a</strong>, as well as the amphiphilic <strong>PS3a</strong> show much stronger response against gram-positive <em>MRSA</em> than that observed for the typical phthalocyanines designed for PDI, namely zinc(II) and palladium(II) complexes, as well as free-base Pcs. Besides, <strong>PS1a</strong>, <strong>PS2a</strong> and <strong>PS3a</strong> show remarkably high activity against the gram-negative <em>E. coli</em>, although weak fungicidal character against fluconazole-resistant <em>C. albicans</em>. Contrasting, the structurally different, amphiphilic <strong>PS4a</strong> shows only slight activity for Gram-positive bacteria, despite its ability to cross cell membrane and reach internal organelles. Still, <strong>PS4a</strong> shows a positive synergistic effect against <em>MRSA</em> when combined with doxycycline, exhibiting an increased activity from about 1.5 to about 4.9 log reduction under the light dose of 30 J/cm<sup>2</sup> and the 0.125 mg/L subinhibitory dose of doxycycline.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.ejmech.2024.117208
Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe
Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-b]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting in vitro target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.
{"title":"Synthesis and Functional Screening of Novel Inhibitors Targeting the HDAC6 Zinc Finger Ubiquitin-Binding Domain","authors":"Silke Geurs, Eleni Staessens, Kato Bredael, Stefaan Borghgraef, Jordy De Ridder, Leentje Persoons, Steven De Jonghe, Dominique Schols, Mandeep K. Mann, Rachel J. Harding, Jorick Franceus, Tom Desmet, Kristof Van Hecke, Dorien Clarisse, Karolien De Bosscher, Matthias D’hooghe","doi":"10.1016/j.ejmech.2024.117208","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117208","url":null,"abstract":"Histone deacetylase 6 (HDAC6) is a promising target for treating neurodegenerative disorders, several cancer types and viral infections. Unique among HDACs, the HDAC6 isoform possesses a zinc finger ubiquitin-binding domain (UBD) crucial for managing misfolded protein aggregates and facilitating viral infection. HDAC6 binds aggregated polyubiquitinated proteins through its UBD, mediating their transport to the aggresome and subsequent removal via autophagy. Despite the importance of the UBD in proteostasis and viral infection, its pharmacological inhibition has been minimally explored thus far, with research largely focused on the deacetylase domain. We synthesized a diverse library of new compounds designed to target the HDAC6-UBD, termed HZUBi, with varied core structures including quinazolinone, oxindole and tetrahydrothiopyrano[4,3-<em>b</em>]indole, aimed at enhancing UBD interaction and extending into the side pocket. New structure-activity relationships were established, computational docking and molecular dynamics studies were performed and the functional impact of selected inhibitors was assessed in the context of multiple myeloma and viral infection. Several new HZUBi could displace a ubiquitin peptide from HDAC6-UBD in a differential manner, although to a lower extent than the literature reference compound HZUBi-3e. Despite exhibiting <em>in vitro</em> target engagement, neither HZUBi-3e nor its ester prodrug HZUBi-1e enhanced proteasome inhibitor-mediated multiple myeloma cell killing. Finally, none of the screened HZUBi triggered anti-viral activity.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Targeted protein degradation (TPD) represents a promising therapeutic approach, encompassing several innovative strategies, including but not limited to proteolysis targeting chimeras (PROTACs), molecular glues, hydrophobic tag tethering degraders (HyTTD), and lysosome-targeted chimeras (LYTACs). Central to TPD are small molecule ligands, which play a critical role in mediating the degradation of target proteins. This review summarizes the current landscape of small molecule ligands for TPD molecules. These small molecule ligands can utilize the proteasome, lysosome, autophagy, or hydrophobic-tagging system to achieve the degradation of target proteins. The article mainly focuses on introducing their design principles, application advantages, and potential limitations. A brief discussion on the development prospects and future directions of TPD technology was also provided.
{"title":"Recent advances in developing targeted protein degraders","authors":"Binbin Cheng, Hongqiao Li, Xiaopeng Peng, Jianjun Chen, Chuxiao Shao, Zhihua Kong","doi":"10.1016/j.ejmech.2024.117212","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117212","url":null,"abstract":"Targeted protein degradation (TPD) represents a promising therapeutic approach, encompassing several innovative strategies, including but not limited to proteolysis targeting chimeras (PROTACs), molecular glues, hydrophobic tag tethering degraders (HyTTD), and lysosome-targeted chimeras (LYTACs). Central to TPD are small molecule ligands, which play a critical role in mediating the degradation of target proteins. This review summarizes the current landscape of small molecule ligands for TPD molecules. These small molecule ligands can utilize the proteasome, lysosome, autophagy, or hydrophobic-tagging system to achieve the degradation of target proteins. The article mainly focuses on introducing their design principles, application advantages, and potential limitations. A brief discussion on the development prospects and future directions of TPD technology was also provided.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.ejmech.2024.117213
Tao Xu, Fangfang Li, Zifan Feng, Chenyu Dang, Yang Yang, Jinrong Wang, Cai-Xia Zang, Xiu-Qi Bao, Shi-Shan Yu, Dan Zhang, Ru-Bing Wang
Insomnia is a mental disorder in which drugs only alleviate the symptoms but also produce adverse effects. Therefore, developing innovative sedative-hypnotic agents is urgent. In this work, twenty-five novel heteroatomic compounds were designed, synthesized, and screened for their sedative activities, structurally featuring the fusion of pyrimidine and carbazole or benzothiazole. Most of the synthesized compounds showed distinct sedative activities in vivo. Among them, 4l displayed excellent sedative and hypnotic properties in the dose range of 0.1 - 2.5 mg/kg, and was superior to diazepam at 5 mg/kg. Mechanism studies showed 4l induced sedative-hypnotic effects via activating cAMP/PKA/CREB signaling pathway. Moreover, 4l possessed appropriate blood brain barrier permeability and excellent bioavailability (F: 74.5 ± 4.5%). Thus, 4l was identified as the lead compound owing to its favorable potency and pharmacokinetic profiles, providing alternative for insomnia drugs development.
{"title":"Design, synthesis and evaluation of pyrimidine derivatives as sedative-hypnotic agents","authors":"Tao Xu, Fangfang Li, Zifan Feng, Chenyu Dang, Yang Yang, Jinrong Wang, Cai-Xia Zang, Xiu-Qi Bao, Shi-Shan Yu, Dan Zhang, Ru-Bing Wang","doi":"10.1016/j.ejmech.2024.117213","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117213","url":null,"abstract":"Insomnia is a mental disorder in which drugs only alleviate the symptoms but also produce adverse effects. Therefore, developing innovative sedative-hypnotic agents is urgent. In this work, twenty-five novel heteroatomic compounds were designed, synthesized, and screened for their sedative activities, structurally featuring the fusion of pyrimidine and carbazole or benzothiazole. Most of the synthesized compounds showed distinct sedative activities <em>in vivo</em>. Among them, <strong>4l</strong> displayed excellent sedative and hypnotic properties in the dose range of 0.1 - 2.5 mg/kg, and was superior to diazepam at 5 mg/kg. Mechanism studies showed <strong>4l</strong> induced sedative-hypnotic effects via activating cAMP/PKA/CREB signaling pathway. Moreover, <strong>4l</strong> possessed appropriate blood brain barrier permeability and excellent bioavailability (F: 74.5 ± 4.5%). Thus, <strong>4l</strong> was identified as the lead compound owing to its favorable potency and pharmacokinetic profiles, providing alternative for insomnia drugs development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1016/j.ejmech.2024.117211
Marion Polomski, Marie Brachet-Botineau, Benjamin Victoir, Cécile Croix, Fabrice Gouilleux, Gildas Prié
Signal Transdcer and Activator of Transcription 5A and 5B (STAT5A/5B) are key effectors of tyrosine kinase oncogenes in myeloid leukemias. It is now clearly evidenced that inhibition of STAT5A/5B not only blocks the growth and survival of myeloid leukemia cells but also overcomes the resistance of leukemic cells to chemotherapy. Previous screening experiments allowed us to identify 17f as a lead compound with promising antileukemic activity that blocks the phosphorylation and transcriptional activity of STAT5A/5B in myeloid leukemia cells addicted to these proteins. In light of these findings, we initiated further pharmacomodulations of 17f to develop new derivatives with enhanced antileukemic activity. Our screening assays identified 14a, an aminopyrimidine derivative of 17f, as a new lead compound that: 1) blocks the growth and survival of myeloid leukemia cells at sub-micromolar concentrations, 2) targets the phosphorylation of STAT5 but also the expression of STAT5B and 3) relieves the resistance of Chronic and Acute Myeloid leukemia cells to conventional chemotherapy.
{"title":"Novel antileukemic compound with sub-micromolar potency against STAT5 addicted myeloid leukemia cells","authors":"Marion Polomski, Marie Brachet-Botineau, Benjamin Victoir, Cécile Croix, Fabrice Gouilleux, Gildas Prié","doi":"10.1016/j.ejmech.2024.117211","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117211","url":null,"abstract":"Signal Transdcer and Activator of Transcription 5A and 5B (STAT5A/5B) are key effectors of tyrosine kinase oncogenes in myeloid leukemias. It is now clearly evidenced that inhibition of STAT5A/5B not only blocks the growth and survival of myeloid leukemia cells but also overcomes the resistance of leukemic cells to chemotherapy. Previous screening experiments allowed us to identify <strong>17f</strong> as a lead compound with promising antileukemic activity that blocks the phosphorylation and transcriptional activity of STAT5A/5B in myeloid leukemia cells addicted to these proteins. In light of these findings, we initiated further pharmacomodulations of <strong>17f</strong> to develop new derivatives with enhanced antileukemic activity<strong>.</strong> Our screening assays identified <strong>14a</strong>, an aminopyrimidine derivative of <strong>17f</strong>, as a new lead compound that: 1) blocks the growth and survival of myeloid leukemia cells at sub-micromolar concentrations, 2) targets the phosphorylation of STAT5 but also the expression of STAT5B and 3) relieves the resistance of Chronic and Acute Myeloid leukemia cells to conventional chemotherapy.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"335 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1016/j.ejmech.2024.117202
Tianyong Tang, Jiaxiang Luo, Dan Zhang, Yang Lu, Wen Liao, Jifa Zhang
Covalent inhibitors provide persistent inhibition while maintaining excellent selectivity and efficacy by creating stable covalent connections with specific amino acids in target proteins. This technique enables the precise inhibition of previously undruggable targets, lowering the frequency of administration and potentially bypassing drug resistance. Because of these advantages, covalent inhibitors have tremendous potential in treating cancer, inflammation, and infectious illnesses, making them extremely important in modern pharmacological research. Covalent inhibitors targeting EGFR, BTK, and KRAS (G12X), which overcome drug resistance and off-target, non-"medicinal" difficulties, as well as covalent inhibitors targeting SARS-CoV-2 Mpro, have paved the way for the development of new antiviral medicines. Furthermore, the use of covalent methods in drug discovery procedures, such as covalent PROTACs, covalent molecular gels, covalent probes, CoLDR, and Dual-targeted covalent inhibitors, preserves these tactics' inherent features while incorporating the advantages of covalent inhibitors. This synthesis opens up new therapeutic opportunities. This review comprehensively examines the use of covalent techniques in drug discovery, emphasizing their transformational potential for future drug development.
{"title":"Innovative design and potential applications of covalent strategy in drug discovery","authors":"Tianyong Tang, Jiaxiang Luo, Dan Zhang, Yang Lu, Wen Liao, Jifa Zhang","doi":"10.1016/j.ejmech.2024.117202","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117202","url":null,"abstract":"Covalent inhibitors provide persistent inhibition while maintaining excellent selectivity and efficacy by creating stable covalent connections with specific amino acids in target proteins. This technique enables the precise inhibition of previously undruggable targets, lowering the frequency of administration and potentially bypassing drug resistance. Because of these advantages, covalent inhibitors have tremendous potential in treating cancer, inflammation, and infectious illnesses, making them extremely important in modern pharmacological research. Covalent inhibitors targeting EGFR, BTK, and KRAS (G12X), which overcome drug resistance and off-target, non-\"medicinal\" difficulties, as well as covalent inhibitors targeting SARS-CoV-2 M<sup>pro</sup>, have paved the way for the development of new antiviral medicines. Furthermore, the use of covalent methods in drug discovery procedures, such as covalent PROTACs, covalent molecular gels, covalent probes, CoLDR, and Dual-targeted covalent inhibitors, preserves these tactics' inherent features while incorporating the advantages of covalent inhibitors. This synthesis opens up new therapeutic opportunities. This review comprehensively examines the use of covalent techniques in drug discovery, emphasizing their transformational potential for future drug development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"70 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1016/j.ejmech.2024.117210
Mason A. Baber, Mya D. Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L. Toogood
PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.
{"title":"Identification of a Selective Pyruvate Dehydrogenase Kinase 1 (PDHK1) Chemical Probe by Virtual Screening","authors":"Mason A. Baber, Mya D. Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L. Toogood","doi":"10.1016/j.ejmech.2024.117210","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117210","url":null,"abstract":"PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth <em>in vitro</em> and <em>in vivo</em>, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound <strong>7</strong> as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound <strong>10</strong>. Structure-activity studies based on <strong>10</strong> identified <strong>17</strong> as a low μM inhibitor of PDHK1 (IC<sub>50</sub> = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound <strong>17</strong> inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify <strong>17</strong> as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1016/j.ejmech.2024.117205
Maloba M.M. Lobe, Saroj Verma, Vaishali M. Patil, Malliga R. Iyer
Myriad signaling pathways are implicated in neuropsychiatric disorders, yet many mechanisms are unknown and current treatment options are limited. The intriguing dynorphin/kappa opioid receptor (KOR) system that is widely distributed throughout the brain appears to be essential in regulating many physiological and pathophysiological processes. This review explores up to date advances on the relationship between the dynorphin/KOR system with a particular focus on the KOR antagonist compounds tested as clinical candidates that could offer potential treatment options for CNS disorders.
{"title":"A review of kappa opioid receptor antagonists and their clinical trial landscape","authors":"Maloba M.M. Lobe, Saroj Verma, Vaishali M. Patil, Malliga R. Iyer","doi":"10.1016/j.ejmech.2024.117205","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117205","url":null,"abstract":"Myriad signaling pathways are implicated in neuropsychiatric disorders, yet many mechanisms are unknown and current treatment options are limited. The intriguing dynorphin/kappa opioid receptor (KOR) system that is widely distributed throughout the brain appears to be essential in regulating many physiological and pathophysiological processes. This review explores up to date advances on the relationship between the dynorphin/KOR system with a particular focus on the KOR antagonist compounds tested as clinical candidates that could offer potential treatment options for CNS disorders.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1016/j.ejmech.2024.117184
Guiyan Huang, Yu Lin, Jianping Zhao, Junlei Zhang, Yuexin Du, Mingyue Xiao, Heng Li, Zhong Chen, Naixin Kang, Ikhlas A. Khan, Yanli Liu, Bin Huang, Qiongming Xu
Corosolic acid (CA), a natural triterpenoid, exhibits various biological activities and is often called a plant-derived insulin due to its significant hypoglycemic effects, making it especially beneficial for individuals with diabetes or high blood glucose levels. However, CA has notable in vitro toxicity, low water solubility, and poor pharmacokinetic properties. To address these limitations, a series of CA derivatives were synthesized, resulting in the identification of derivative H26, which demonstrates a significantly enhanced hypoglycemic effect, reduced toxicity, and improved pharmacokinetic characteristics compared to CA. To identify the target protein of CA and investigate its therapeutic potential, a chemical probe derived from natural products, called CA-biotin, was designed and synthesized. By employing an avidin-biotin affinity binding system, we distinguished the differential protein bands between CA-biotin and biotin. This quantitative proteomic analysis revealed, for the first time, that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) directly binds to CA. The interaction between H26 and MCCC1 was examined in vitro. The research on the mechanisms by which CA and H26 address Type 2 diabetes mellitus (T2DM) concentrated on the insulin resistance signaling pathway, specifically targeting MCCC1. The results indicated that H26 shows significant promise as a potential hypoglycemic agent, while MCCC1 may serve as a valuable target for addressing insulin resistance. This presents a promising opportunity for developing new medications aimed at improving the health of patients with type 2 diabetes mellitus (T2DM) or hyperglycemia.
{"title":"Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice","authors":"Guiyan Huang, Yu Lin, Jianping Zhao, Junlei Zhang, Yuexin Du, Mingyue Xiao, Heng Li, Zhong Chen, Naixin Kang, Ikhlas A. Khan, Yanli Liu, Bin Huang, Qiongming Xu","doi":"10.1016/j.ejmech.2024.117184","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117184","url":null,"abstract":"Corosolic acid (CA), a natural triterpenoid, exhibits various biological activities and is often called a plant-derived insulin due to its significant hypoglycemic effects, making it especially beneficial for individuals with diabetes or high blood glucose levels. However, CA has notable in vitro toxicity, low water solubility, and poor pharmacokinetic properties. To address these limitations, a series of CA derivatives were synthesized, resulting in the identification of derivative H26, which demonstrates a significantly enhanced hypoglycemic effect, reduced toxicity, and improved pharmacokinetic characteristics compared to CA. To identify the target protein of CA and investigate its therapeutic potential, a chemical probe derived from natural products, called CA-biotin, was designed and synthesized. By employing an avidin-biotin affinity binding system, we distinguished the differential protein bands between CA-biotin and biotin. This quantitative proteomic analysis revealed, for the first time, that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) directly binds to CA. The interaction between H26 and MCCC1 was examined in vitro. The research on the mechanisms by which CA and H26 address Type 2 diabetes mellitus (T2DM) concentrated on the insulin resistance signaling pathway, specifically targeting MCCC1. The results indicated that H26 shows significant promise as a potential hypoglycemic agent, while MCCC1 may serve as a valuable target for addressing insulin resistance. This presents a promising opportunity for developing new medications aimed at improving the health of patients with type 2 diabetes mellitus (T2DM) or hyperglycemia.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"123 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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