{"title":"Development of novel ALOX15 inhibitors combining dual machine learning filtering and fragment substitution optimisation approaches, molecular docking and dynamic simulation methods.","authors":"Yinglin Liao, Peng Cao, Lianxiang Luo","doi":"10.1080/14756366.2024.2301756","DOIUrl":"10.1080/14756366.2024.2301756","url":null,"abstract":"<p><p>The oxidation of unsaturated lipids, facilitated by the enzyme Arachidonic acid 15-lipoxygenase (ALOX15), is an essential element in the development of ferroptosis. This study combined a dual-score exclusion strategy with high-throughput virtual screening, naive Bayesian and recursive partitioning machine learning models, the already established ALOX15 inhibitor i472, and a docking-based fragment substitution optimisation approach to identify potential ALOX15 inhibitors, ultimately leading to the discovery of three FDA-approved drugs that demonstrate optimal inhibitory potential against ALOX15. Through fragment substitution-based optimisation, seven new inhibitor structures have been developed. To evaluate their practicality, ADMET predictions and molecular dynamics simulations were performed. In conclusion, the compounds found in this study provide a novel approach to combat conditions related to ferroptosis-related injury by inhibiting ALOX15.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301756"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424925","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}
Ender Simsek, Asuman Sunguroglu, Ahmet Kilic, Nurbanu Özgültekin, O Ozensoy Guler
{"title":"Effects of thymoquinone and the curcumin analog EF-24 on the activity of the enzyme paraoxonase-1 in human glioblastoma cells U87MG.","authors":"Ender Simsek, Asuman Sunguroglu, Ahmet Kilic, Nurbanu Özgültekin, O Ozensoy Guler","doi":"10.1080/14756366.2024.2339901","DOIUrl":"10.1080/14756366.2024.2339901","url":null,"abstract":"<p><p>The spices and aromatic herbs were used not only in cooking to add flavour and smell to dishes but also for medicinal use. Nigella sativa, also called black cumin, is one of the species that contains an important bioactive component, thymoquinone (TQ), which has antioxidant, anti-inflammatory, antimicrobial, and antidiabetic effects. Curcuma longa, which also includes curcumin, has numerous anti-cancer properties. However, the bioavailability of curcumin is lower than that of its analogs. An analog of curcumin (EF-24), which has better bioavailability than curcumin, is capable of exerting a high anti-cancer effect. In our study, we determined the effects of PON1 enzyme activity on the proliferation and aggressiveness of glioblastoma cancer treated with TQ and EF-24 from lysates of the glioblastoma cell line U87MG. The results were determined as increased PON1 activity after treatment with TQ and EF-24 in the U87MG cell line (<i>p</i> < 0.0001).</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2339901"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11172254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306105","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}
Viviana De Luca, Simone Giovannuzzi, Clemente Capasso, Claudiu T Supuran
{"title":"Cloning, expression, and purification of an α-carbonic anhydrase from <i>Toxoplasma gondii</i> to unveil its kinetic parameters and anion inhibition profile.","authors":"Viviana De Luca, Simone Giovannuzzi, Clemente Capasso, Claudiu T Supuran","doi":"10.1080/14756366.2024.2346523","DOIUrl":"10.1080/14756366.2024.2346523","url":null,"abstract":"<p><p>Toxoplasmosis, induced by the intracellular parasite <i>Toxoplasma gondii</i>, holds considerable implications for global health. While treatment options primarily focusing on folate pathway enzymes have notable limitations, current research endeavours concentrate on pinpointing specific metabolic pathways vital for parasite survival. Carbonic anhydrases (CAs, EC 4.2.1.1) have emerged as potential drug targets due to their role in fundamental reactions critical for various protozoan metabolic processes. Within <i>T. gondii</i>, the Carbonic Anhydrase-Related Protein (TgCA_RP) plays a pivotal role in rhoptry biogenesis. Notably, α-CA (TcCA) from another protozoan, <i>Trypanosoma cruzi</i>, exhibited considerable susceptibility to classical CA inhibitors (CAIs) such as anions, sulphonamides, thiols, and hydroxamates. Here, the recombinant DNA technology was employed to synthesise and clone the identified gene in the <i>T. gondii</i> genome, which encodes an α-CA protein (Tg_CA), with the purpose of heterologously overexpressing its corresponding protein. Tg_CA kinetic constants were determined, and its inhibition patterns explored with inorganic metal-complexing compounds, which are relevant for rational compound design. The significance of this study lies in the potential development of innovative therapeutic strategies that disrupt the vital metabolic pathways crucial for <i>T. gondii</i> survival and virulence. This research may lead to the development of targeted treatments, offering new approaches to manage toxoplasmosis.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2346523"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283871","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}
Xing Jin, Yuting Wang, Jing Chen, Miaomiao Niu, Yang Yang, Qiaoxuan Zhang, Guangyu Bao
{"title":"Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and <i>in vitro</i> and <i>in vivo</i> biological activity evaluations.","authors":"Xing Jin, Yuting Wang, Jing Chen, Miaomiao Niu, Yang Yang, Qiaoxuan Zhang, Guangyu Bao","doi":"10.1080/14756366.2023.2289355","DOIUrl":"10.1080/14756366.2023.2289355","url":null,"abstract":"<p><p>Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC<sub>50</sub> = 0.08 ± 0.03 μM) and HDAC2 (IC<sub>50</sub> = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2289355"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498512","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}
{"title":"3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines inhibit tubulin polymerisation and act as anticancer agents.","authors":"Chao Wang, Yujing Zhang, Shanbo Yang, Lingyu Shi, Yutao Xiu, Yudong Wu, Hongfei Jiang","doi":"10.1080/14756366.2023.2286939","DOIUrl":"10.1080/14756366.2023.2286939","url":null,"abstract":"<p><p>A series of <i>cis-</i>restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound <b>9p</b>, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that <b>9p</b> potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, <b>9p</b> could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that <b>9p</b> conformed well to the Lipinski's rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2286939"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138804867","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}
Elisa Rojas-Prats, Loreto Martinez-Gonzalez, Carmen Gil, David Ramírez, Ana Martinez
{"title":"Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase.","authors":"Elisa Rojas-Prats, Loreto Martinez-Gonzalez, Carmen Gil, David Ramírez, Ana Martinez","doi":"10.1080/14756366.2024.2301767","DOIUrl":"10.1080/14756366.2024.2301767","url":null,"abstract":"<p><p>Cell division cycle 7 kinase (CDC7) has been found overexpressed in many cancer cell lines being also one of the kinases involved in the nuclear protein TDP-43 phosphorylation <i>in vivo</i>. Thus, inhibitors of CDC7 are emerging drug candidates for the treatment of oncological and neurodegenerative unmet diseases. All the known CDC7 inhibitors are ATP-competitives, lacking of selectivity enough for success in clinical trials. As allosteric sites are less conserved among kinase proteins, discovery of allosteric modulators of CDC7 is a great challenge and opportunity in this field.Using different computational approaches, we have here identified new druggable cavities on the human CDC7 structure and subsequently selective CDC7 inhibitors with allosteric modulation mainly targeting the pockets where the interaction between this kinase and its activator DBF4 takes place.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2301767"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10786434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417218","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}
Mateusz Olszewski, Natalia Maciejewska, Anoop Kallingal, Agnieszka Chylewska, Aleksandra M Dąbrowska, Małgorzata Biedulska, Mariusz Makowski, José M Padrón, Maciej Baginski
{"title":"Palindromic carbazole derivatives: unveiling their antiproliferative effect via topoisomerase II catalytic inhibition and apoptosis induction.","authors":"Mateusz Olszewski, Natalia Maciejewska, Anoop Kallingal, Agnieszka Chylewska, Aleksandra M Dąbrowska, Małgorzata Biedulska, Mariusz Makowski, José M Padrón, Maciej Baginski","doi":"10.1080/14756366.2024.2302920","DOIUrl":"10.1080/14756366.2024.2302920","url":null,"abstract":"<p><p>Human DNA topoisomerases are essential for crucial cellular processes, including DNA replication, transcription, chromatin condensation, and maintenance of its structure. One of the significant strategies employed in cancer treatment involves the inhibition of a specific type of topoisomerase, known as topoisomerase II (Topo II). Carbazole derivatives, recognised for their varied biological activities, have recently become a significant focus in oncological research. This study assesses the efficacy of three symmetrically substituted carbazole derivatives: 2,7-Di(2-furyl)-9H-carbazole (<b>27a</b>), 3,6-Di(2-furyl)-9H-carbazole (<b>36a</b>), and 3,6-Di(2-thienyl)-9H-carbazole (<b>36b</b>) - as anticancer agents. Among investigated carbazole derivatives, compound 3,6-di(2-furyl)-9H-carbazole bearing two furan moieties emerged as a novel catalytic inhibitor of Topo II. Notably, 3,6-di(2-furyl)-9H-carbazole effectively selectively inhibited the relaxation and decatenation activities of Topo IIα, with minimal effects on the IIβ isoform. These findings underscore the potential of compound 3,6-Di(2-furyl)-9H-carbazole as a promising lead candidate warranting further investigation in the realm of anticancer drug development.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2302920"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466698","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}
Nirvana A Gohar, Eman A Fayed, Yousry A Ammar, Ola A Abu Ali, Ahmed Ragab, Amal M Mahfoz, Moustafa S Abusaif
{"title":"Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting <i>α</i>-amylase, and <i>α</i>-glucosidase: synthesis, molecular docking, and ADMET studies.","authors":"Nirvana A Gohar, Eman A Fayed, Yousry A Ammar, Ola A Abu Ali, Ahmed Ragab, Amal M Mahfoz, Moustafa S Abusaif","doi":"10.1080/14756366.2024.2367128","DOIUrl":"10.1080/14756366.2024.2367128","url":null,"abstract":"<p><p>Inhibition of α-glucosidase and <i>α</i>-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-<i>b</i>] quinoxalines-carrying thiazole hybrids <b>1-17</b> were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds <b>4</b>, <b>6</b>, <b>8</b>, and <b>16</b> were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against <i>α</i>-glucosidase and <i>α</i>-amylase enzymes <i>in vitro</i>. The four hybrids <b>4</b>, <b>6</b>, <b>8</b>, and <b>16</b> represented moderate to potent activity with IC<sub>50</sub> values 0.982 ± 0.04, to 10.19 ± 0.21 for <i>α</i>-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 μM for <i>α</i>-amylase inhibition when compared to the standard medication acarbose with IC<sub>50</sub>=0.316 ± 0.02 μM for <i>α</i>-glucosidase inhibition and 31.56 ± 1.33 μM for <i>α</i>-amylase inhibition. Docking studies as well as <i>in silico</i> ADMT were done.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2367128"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC467095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446338","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}
Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli
{"title":"Watermelon: setup and validation of an <i>in silico</i> fragment-based approach.","authors":"Miriana Di Stefano, Salvatore Galati, Lisa Piazza, Francesca Gado, Carlotta Granchi, Marco Macchia, Antonio Giordano, Tiziano Tuccinardi, Giulio Poli","doi":"10.1080/14756366.2024.2356179","DOIUrl":"10.1080/14756366.2024.2356179","url":null,"abstract":"<p><p>We present a new computational approach, named <i>Watermelon</i>, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the <i>Watermelon</i> approach.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2356179"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306106","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}
Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad
{"title":"Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases.","authors":"Mohamed Elagawany, Lina M A Abdel Ghany, Tarek S Ibrahim, Abdulrhman S Alharbi, Mohamed S Abdel-Aziz, Eman M El-Labbad, Noha Ryad","doi":"10.1080/14756366.2024.2311157","DOIUrl":"10.1080/14756366.2024.2311157","url":null,"abstract":"<p><p>Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds <b>5</b>, <b>4b</b>, and <b>4a</b> possessed potent cytotoxic activity against PC-3 cells with IC<sub>50</sub> 3.56, 8.99, and 10.22 µM, respectively. Compound <b>4c</b> displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC<sub>50</sub> 8.5 µM. Moreover, compound <b>5</b> exhibited potent inhibitory activity on EFGR with IC<sub>50</sub> 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the <i>in vitro</i> results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound <b>5</b> decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound <b>5</b> caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"39 1","pages":"2311157"},"PeriodicalIF":5.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10866054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722893","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}