Journal of Enzyme Inhibition and Medicinal Chemistry最新文献_第5页

Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation. 通过虚拟筛选和生物学评价鉴定BCKDK的推定变构抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2023-12-07 DOI: 10.1080/14756366.2023.2290458

Chunqiong Li, Quanjun Yang, Li Zhang

{"title":"Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.","authors":"Chunqiong Li, Quanjun Yang, Li Zhang","doi":"10.1080/14756366.2023.2290458","DOIUrl":"10.1080/14756366.2023.2290458","url":null,"abstract":"Abnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 μM and 1.86 μM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2290458"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases. 拓展 WWP1 和 WWP2 HECT E3 连接酶的抑制剂空间。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI: 10.1080/14756366.2024.2394895

Ashley P Dudey, Jake M Rigby, Gregory R Hughes, G Richard Stephenson, Thomas E Storr, Andrew Chantry, Andrew M Hemmings

{"title":"Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.","authors":"Ashley P Dudey, Jake M Rigby, Gregory R Hughes, G Richard Stephenson, Thomas E Storr, Andrew Chantry, Andrew M Hemmings","doi":"10.1080/14756366.2024.2394895","DOIUrl":"10.1080/14756366.2024.2394895","url":null,"abstract":"The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2394895"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes. 用于治疗 II 型糖尿病的新型喹喔啉衍生物的合成、分子建模和生物学评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-23 DOI: 10.1080/14756366.2024.2395985

Fatmah Ali S Alasmary, Dalal A Abdullah, Vijay H Masand, Abir Ben Bacha, Abdelsattar Mansour Omar Ebeid, Moustafa E El-Araby, Ahmed M Alafeefy

{"title":"Synthesis, molecular modelling, and biological evaluation of novel quinoxaline derivatives for treating type II diabetes.","authors":"Fatmah Ali S Alasmary, Dalal A Abdullah, Vijay H Masand, Abir Ben Bacha, Abdelsattar Mansour Omar Ebeid, Moustafa E El-Araby, Ahmed M Alafeefy","doi":"10.1080/14756366.2024.2395985","DOIUrl":"10.1080/14756366.2024.2395985","url":null,"abstract":"Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2395985"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus. 针对 SARS-CoV-2-Omicron 病毒的二氢杨梅素衍生物的设计、合成和生物活性评价。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-08-29 DOI: 10.1080/14756366.2024.2390909

Cong Wu, Qi Jiang, Hui Zhong, Xudong Zhou, Leping Liu, Tong Pan, Chao Liu, Wei Wang, Wenbing Sheng

{"title":"Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus.","authors":"Cong Wu, Qi Jiang, Hui Zhong, Xudong Zhou, Leping Liu, Tong Pan, Chao Liu, Wei Wang, Wenbing Sheng","doi":"10.1080/14756366.2024.2390909","DOIUrl":"https://doi.org/10.1080/14756366.2024.2390909","url":null,"abstract":"An oxidising and substituting one-pot reaction strategy has been developed to synthesise dihydromyricetin derivatives with the aim of enhancing the inhibitory activity of dihydromyricetin against SARS-CoV-2. Different ω-methoxy-ω-oxeylkyl was introduced in C7-OH site and yielded eight analogs, all of them showed good inhibitory activity against SARS-CoV-2 3CLpro with IC50 values ranging from 0.72 to 2.36 μM. In the Vero E6-cell, compound 3 has a good activity of anti-SARS-CoV-2 virus (Omicron virus BA.5) in the prevention model, with an EC50 of 15.84 μM, and so do compound 10 in the therapeutic model, with an EC50 of 11.52 μM. The results suggest that the introduction of long chain ω-oxeylkyl at C7-OH facilitate the inhibition of viral replication in the therapeutic model, which is consistent with the binding energies predicted from molecular docking conclusions. It implies that dihydromyricetin derivatives have the potential to become effective inhibitors of SARS-CoV-2 Omicron and other viruses.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2390909"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives. 通过合理设计和合成硝氟酸衍生物，探索 TEAD 的结构和生物学特性。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1080/14756366.2024.2419925

Yong-Sung Choi, Yoon-Jung Kim, Yeram Jeon, Jong Soon Kang, Juhee Lee, Eunmi Hong, Young-Hoon Park, Wantae Kim, Boksik Cha, Raok Jeon

{"title":"Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives.","authors":"Yong-Sung Choi, Yoon-Jung Kim, Yeram Jeon, Jong Soon Kang, Juhee Lee, Eunmi Hong, Young-Hoon Park, Wantae Kim, Boksik Cha, Raok Jeon","doi":"10.1080/14756366.2024.2419925","DOIUrl":"10.1080/14756366.2024.2419925","url":null,"abstract":"Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2419925"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Computational fragment-based drug design of potential Glo-I inhibitors. 基于计算片段的潜在 Glo-I 抑制剂药物设计。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-22 DOI: 10.1080/14756366.2024.2301758

Roaa S Bibars, Qosay A Al-Balas

引用次数: 0

Identification of potential inhibitors against Staphylococcus aureus shikimate dehydrogenase through virtual screening and susceptibility test. 通过虚拟筛选和药敏试验鉴定金黄色葡萄球菌莽草酸脱氢酶的潜在抑制剂。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-01-17 DOI: 10.1080/14756366.2024.2301768

Mengfan Zhu, Jinfeng Qu, Qi Deng

{"title":"Identification of potential inhibitors against Staphylococcus aureus shikimate dehydrogenase through virtual screening and susceptibility test.","authors":"Mengfan Zhu, Jinfeng Qu, Qi Deng","doi":"10.1080/14756366.2024.2301768","DOIUrl":"10.1080/14756366.2024.2301768","url":null,"abstract":"Staphylococcus aureus shikimate dehydrogenase (SaSDH) plays a crucial role in the growth of Staphylococcus aureus (S. aureus), but absent in mammals and therefore a potential target for antibacterial drugs to treat drug-resistant S. aureus infection. In this study, a 3D model of SaSDH was constructed by homology modelling and inhibitors of SaSDH were screened through virtual screening. (-)-Gallocatechin gallate and rhodiosin were identified as inhibitors with Kis of 2.47 μM and 73.38 μM, respectively. Molecular docking and isothermal titration calorimetry showed that both inhibitors interact with SaSDH with a KD of 44.65 μM for (-)-gallocatechin gallate and 16.45 μM for rhodiosin. Both inhibitors had antibacterial activity, showing MICs of 50 μg/mL for (-)-gallocatechin gallate and 250 μg/mL for rhodiosin against S. aureus. The current findings have the potential for identification of drugs to treat S. aureus infections by targeting SaSDH.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301768"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10798293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 comprehensive investigation of the anion inhibition profile of a β-carbonic anhydrase from Acinetobacter baumannii for crafting innovative antimicrobial treatments. 全面研究鲍曼不动杆菌β-碳酸酐酶的阴离子抑制谱，以开发创新的抗菌疗法。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-07-16 DOI: 10.1080/14756366.2024.2372731

Viviana De Luca, Simone Giovannuzzi, Claudiu T Supuran, Clemente Capasso

{"title":"A comprehensive investigation of the anion inhibition profile of a β-carbonic anhydrase from Acinetobacter baumannii for crafting innovative antimicrobial treatments.","authors":"Viviana De Luca, Simone Giovannuzzi, Claudiu T Supuran, Clemente Capasso","doi":"10.1080/14756366.2024.2372731","DOIUrl":"10.1080/14756366.2024.2372731","url":null,"abstract":"This study refers to the intricate world of Acinetobacter baumannii, a resilient pathogenic bacterium notorious for its propensity at antibiotic resistance in nosocomial infections. Expanding upon previous findings that emphasised the bifunctional enzyme PaaY, revealing unexpected γ-carbonic anhydrase (CA) activity, our research focuses on a different class of CA identified within the A. baumannii genome, the β-CA, designated as 𝛽-AbauCA (also indicated as CanB), which plays a crucial role in the resistance mechanism mediated by AmpC beta-lactamase. Here, we cloned, expressed, and purified the recombinant 𝛽-AbauCA, unveiling its distinctive kinetic properties and inhibition profile with inorganic anions (classical CA inhibitors). The exploration of 𝛽-AbauCA not only enhances our understanding of the CA repertoire of A. baumannii but also establishes a foundation for targeted therapeutic interventions against this resilient pathogen, promising advancements in combating its adaptability and antibiotic resistance.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2372731"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Antifungal and anti-biofilm effects of hydrazone derivatives on Candida spp. 腙衍生物对念珠菌属的抗真菌和抗生物膜作用

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-26 DOI: 10.1080/14756366.2024.2429109

Pierre Popczyk, Alina Ghinet, Clovis Bortolus, Laure Kamus, Marc F Lensink, Jérôme de Ruyck, Boualem Sendid, Faustine Dubar

引用次数: 0

Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways. 发现通过调节 MAPK 和 Akt 通路作为中性粒细胞炎症抑制剂的 1,3 二甲基丙-2-烯-1-酮衍生物。

IF 5.6 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-12-01 Epub Date: 2024-09-19 DOI: 10.1080/14756366.2024.2402988

Mohammad Abdel-Halim, Dalia S El-Gamil, Mennatallah A Hammam, Mohamed El-Shazly, Yi-Hsuan Wang, Po-Hsiung Kung, Yu-Cheng Chen, Michal Korinek, Ashraf H Abadi, Matthias Engel, Tsong-Long Hwang

{"title":"Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways.","authors":"Mohammad Abdel-Halim, Dalia S El-Gamil, Mennatallah A Hammam, Mohamed El-Shazly, Yi-Hsuan Wang, Po-Hsiung Kung, Yu-Cheng Chen, Michal Korinek, Ashraf H Abadi, Matthias Engel, Tsong-Long Hwang","doi":"10.1080/14756366.2024.2402988","DOIUrl":"10.1080/14756366.2024.2402988","url":null,"abstract":"Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects: one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound 6a being most effective (IC50 values of 1.23 and 1.37 μM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound 26a (IC50 of 1.56 μM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2402988"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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