RSC medicinal chemistry最新文献

{"title":"Routing NSAIDs into the Golgi apparatus induces autophagy and apoptosis in cancer cells†","authors":"Aditi, Tripti Mishra, Asima Sahu, Unnati Modi, Dhiraj Bhatia and Sudipta Basu","doi":"10.1039/D5MD00215J","DOIUrl":"10.1039/D5MD00215J","url":null,"abstract":"<p >The Golgi apparatus (GA), a critical sub-cellular organelle, plays a pivotal role in numerous biological signaling pathways, including the post-translational modification of proteins and their secretion to various cellular destinations. Dysregulation of GA function is implicated in the development of several diseases, including cancer. As a result, detouring clinically approved drugs into the GA for an enhanced anti-cancer effect remained a major challenge. To address this, herein, we designed and synthesized NSAID-based conjugates incorporating a fluorophore (1,8-naphthalimide) and a Golgi-homing moiety (phenylsulfonamide). Screening these conjugates in cervical (HeLa) and colon (HCT-116) cancer cells identified a particularly promising candidate: the ibuprofen-1,8-naphthalimide-phenylsulfonamide conjugate (<strong>7a</strong>) which exhibited significant cytotoxicity against HCT-116 cells as well as in lung cancer (A549), colon carcinoma (Caco-2) and breast cancer (MCF7) cells. Interestingly, compound <strong>7a</strong> self-assembled into nanoscale petal-like structures in water and efficiently homed into the GA as well as in the endoplasmic reticulum (ER) within 30 min to induce morphological damage to the GA. Compound <strong>7a</strong> mediated GA damage increased the expression of Beclin and LC3-I/II proteins to induce autophagy which was further inhibited by chloroquine (CQ) and bafilomycin A1 (BFA) leading to remarkable HCT-116 cell death in combination with <strong>7a</strong>. Moreover, compound <strong>7a</strong> triggered apoptosis by downregulating anti-apoptotic Bcl-2 and Cas-3 as well as cleaving PARP proteins in HCT-116 cells, while demonstrating no toxicity towards non-cancerous human retinal pigment epithelial cells (RPE-1). Interestingly, compound <strong>7a</strong> also reduced the size and growth of the HeLa 3D spheroids significantly after 72 h. This ibuprofen derivative (<strong>7a</strong>) holds promise as a valuable tool for illuminating the chemical biology of the GA in cancer cells and as a potential candidate for anti-cancer therapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4767-4773"},"PeriodicalIF":3.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-aided discovery of triazolothiadiazoles as DYRK1A-targeted neuroprotective agents†","authors":"Xinxin Si, Yaling Wang, Nianzhuang Qiu, Chenliang Qian, Bochao Yang, Hongwei Jin, Hao Wang, Xuehui Zhang and Jie Xia","doi":"10.1039/D5MD00289C","DOIUrl":"10.1039/D5MD00289C","url":null,"abstract":"<p >Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a promising target for drug discovery against neurological diseases. So far, no DYRK1A inhibitor has been approved for clinical use, partly due to the lack of effective and safe chemotypes. In this study, by using a computer-aided drug design strategy and DYRK1A inhibition assay, we were able to identify a novel DYRK1A inhibitor, <em>i.e.</em>, compound <strong>Y16-5</strong> (Specs ID: <strong>AO-365/43472821</strong>) with an IC<small>₅₀</small> value of 0.29 μM. The molecular docking and molecular dynamics simulations uncovered the binding details of compound <strong>Y16-5</strong> that included hydrogen bonds with Leu241, Lys188 and Lys167. According to the kinome analysis, compound <strong>Y16-5</strong> was highly selective to DYRK1A. Further cell-based assays have shown that compound <strong>Y16-5</strong> could protect human neuroblastoma cell line SH-SY5Y from okadaic acid (OA)-induced injury. In terms of the molecular mechanism, compound <strong>Y16-5</strong> decreased tau (pSer396)/tau and Aβ<small>_1–42</small> protein expression highly related to Alzheimer's disease. Further <em>in vitro</em> druglikeness evaluation has demonstrated that (1) compound <strong>Y16-5</strong> was not toxic to SH-SY5Y and HL-7702 cells (CC<small>₅₀</small> &gt; 100 μM), and (2) compound <strong>Y16-5</strong> could permeate the blood–brain-barrier, with a permeability value of 31.52 (×10<small>⁻⁶</small> cm s<small>⁻¹</small>). Taken together, we have discovered a potent DYRK1A inhibitor <strong>Y16-5</strong> with neuroprotective activity by <em>in silico</em> screening and <em>in vitro</em> bioassays.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4731-4741"},"PeriodicalIF":3.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the anticancer efficacy and impact on energy metabolism of dual-core gold(i) complex BGC2a†","authors":"Hai-Ling Gao, Wenwen Ding, Zhi-Xin Shen and Qingbin Cui","doi":"10.1039/D5MD00477B","DOIUrl":"10.1039/D5MD00477B","url":null,"abstract":"<p >Dual-core gold(<small>I</small>) complex <strong>BGC2a</strong> has been shown to have superior anticancer potential to the clinical candidate auranofin (AF) in non-small lung cancer cells <em>in vitro</em> and <em>in vivo</em>. In this work, we further investigate <strong>BGC2a</strong>'s potential as an anticancer candidate in a set of different cancer cell lines as well as its safety profile in normal cells. <strong>BGC2a</strong> (IC<small>₅₀</small> ranging from 0.33 to 0.78 μM) consistently showed higher cytotoxicity in six cancer cell lines than AF (IC<small>₅₀</small> ranging from 0.56 to 1.41 μM), without increasing its toxic effects in normal HS-5 and natural killer T (NKT) cells. <strong>BGC2a</strong> preferably killed KRAS-on cells over KRAS-off cells, and it was highly potent in inhibiting cancer stem-like cells, as it alone or combined with celecoxib reduced the colony formations of DLD1, PANC1, and A549 cells in a dose-dependent manner. Similar colony-suppressing effects were also identified in glioma stem cells GSC11 and GSC23. Pretreatment of <strong>BGC2a</strong> (1 μM, 24 h) could significantly inhibit the tumor formation <em>in vivo</em>. The mechanistic study indicated that <strong>BGC2a</strong> preferably inhibited the TrxR activity in mitochondria, and it reduced lactate production, which was mediated partially by inhibiting GAPDH. <strong>BGC2a</strong> induced apoptosis of HCT116 cells <em>via</em> a mitochondria-mediated mechanism and reduced the tumor growth of the HCT116 xenograft model without altering the body weight of treated mice. These findings further support <strong>BGC2a</strong> as a promising novel therapy for cancer treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 4859-4871"},"PeriodicalIF":3.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144761166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and apoptotic antiproliferative efficacy of new quinazoline/1,3,4-oxadiazole-2-thione derived EGFR/HER-2 dual inhibitors with anti-breast cancer activity†","authors":"Hesham A. M. Gomaa, Mohamed E. Shaker, Sami I. Alzarea, Tariq G. Alsahli, Abdullah Salah Alanazi, Fatma A. M. Mohamed, Mashael Naif Alanazi, Hesham A. Abou-Zied, Alshaimaa Abdelmoez, Stefan Brase, Bahaa G. M. Youssif and Mohamed T.-E. Maghraby","doi":"10.1039/D5MD00454C","DOIUrl":"10.1039/D5MD00454C","url":null,"abstract":"<p >A series of new multi-target inhibitors derived from quinazoline and 1,3,4-oxadiazole-2-thione were designed, synthesized, and tested <em>in vitro</em> for their antiproliferative efficacy. Compounds <strong>7a</strong>, <strong>7e</strong>, <strong>7h</strong>, <strong>7k</strong>, and <strong>7l</strong> exhibited the most significant antiproliferative activity, with GI<small>₅₀</small> values of 30, 26, 39, 35, and 32 nM, respectively. The <em>in vitro</em> inhibitory effects of compounds <strong>7a</strong>, <strong>7e</strong>, <strong>7h</strong>, <strong>7k</strong>, and <strong>7l</strong> against the EGFR, BRAF<small>^V600E</small>, and HER-2 isozymes were examined. Compounds <strong>7h</strong> and <strong>7k</strong> were identified as the most potent multi-target inhibitors, with IC<small>₅₀</small> values of 76 ± 4 (EGFR), 33 ± 2 (HER-2), and 48 ± 3 (BRAF<small>^V600E</small>) for <strong>7h</strong>, and 71 ± 4 (EGFR), 29 ± 1 (HER-2), and 45 ± 3 (BRAF<small>^V600E</small>) for <strong>7k</strong>, respectively. Compounds <strong>7h</strong> and <strong>7k</strong> markedly elevated the levels of caspase-3, caspase-8, and Bax proteins in the MCF-7 cancer cell line, while simultaneously reducing the levels of the anti-apoptotic protein Bcl-2. Computational studies provided insights into the binding interactions and stability of <strong>7k</strong> with EGFR and HER-2. Density functional theory (DFT) and molecular electrostatic potential (MEP) analyses further confirmed the electronic stability and reactivity of FT-<strong>7k</strong>, highlighting its optimized structural and electronic properties for receptor binding. ADME predictions indicated that <strong>7k</strong> possesses favorable pharmacokinetic properties, making it a promising candidate for further development.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4297-4315"},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFRAP: a predictive machine learning model for assessing small molecule activity against the epidermal growth factor receptor","authors":"Ashish Gupta, Amarinder S. Thind and Rituraj Purohit","doi":"10.1039/D5MD00361J","DOIUrl":"10.1039/D5MD00361J","url":null,"abstract":"<p >Epidermal growth factor receptor (EGFR) is a membrane-bound protein that interacts with epidermal growth factor, triggering receptor dimerization and tyrosine autophosphorylation, subsequently promoting cell proliferation. EGFR-associated pathways regulate cell housekeeping functions like growth, division, and apoptosis. However, the mutations/overexpression of EGFR cause unrestrained cell differentiation, leading to tumorigenesis. This study proposes a machine-learning-based tool, EGFR<small>^AP</small>, to compute novel molecules' biological activities (pIC<small>₅₀</small>) against EGFR. The tool is based on a robust quantitative structure–activity relationship (QSAR) model, trained on a large dataset of existing EGFR inhibitors using multiple machine learning algorithms. The extra trees regressor (ET) model showed promising results for the training dataset with an <em>R</em><small>²</small> value of 0.99, an RMSE value of 0.07 and an MAE of 0.009. The Pearson correlation between the observed and predicted pIC<small>₅₀</small> values of the training set inhibitors was also very substantial, <em>i.e.</em> 0.99. The model was then validated using a test dataset, and the findings were satisfactory. An <em>R</em><small>²</small> value of 0.67, an RMSE of 0.89 and an MAE of 0.61 were detected for the test dataset, and the Pearson correlation coefficient of observed/predicted pIC<small>₅₀</small> values was 0.82. The model was probed for overfitting using 10-fold cross-validation, and a series of structure-based drug design experiments were performed to validate the tool's predictions. The findings backed up the model's performance. This tool will be of significant importance to medicinal chemists in identifying promising EGFR inhibitors.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4415-4426"},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and investigation of thieno[2,3-b]pyridines that restore activity of topotecan†","authors":"Emily K. Paulin, Natalie A. Haverkate, Petr Tomek, Jagdish K. Jaiswal, Emily Dobbs, Jumana Nahhas, Euphemia Leung, Xiang Gao, Lin-Kun An, Lisa I. Pilkington and David Barker","doi":"10.1039/D5MD00509D","DOIUrl":"10.1039/D5MD00509D","url":null,"abstract":"<p >Chemoresistance poses a major challenge to the successful outcome of cancer chemotherapy by reducing or eliminating drug efficacy. Anti-cancer medicines causing DNA damage by inhibiting topoisomerase I (TOP1) are particularly susceptible as cancers adopt resistance mechanisms. Drugs countering these resistance mechanisms can be introduced to the regimen and increase the vulnerability of cancer cells to TOP1 inhibitors. DNA repair enzymes such as tyrosyl-DNA phosphodiesterase 1 (TDP1) emerge as promising drug targets for restoring activity of TOP1 inhibitors. Herein, we describe the synthesis and biological evaluation of thieno[2,3-<em>b</em>]pyridines that markedly sensitised H460 lung cancer cells to the TOP1 inhibitor topotecan. Surprisingly, TDP1 knockout further potentiated the synergy between thieno[2,3-<em>b</em>]pyridines and topotecan suggesting that a complex network of DNA repair pathways rather than TDP1 alone mediates the sensitising effect. SAR studies have identified structural motifs in this compound class that led to optimal performance, identifying leads for development into clinical chemosensitisers of TOP1 poisons.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4377-4389"},"PeriodicalIF":3.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and characterization of novel pyridazin-3-one derivatives: in vitro vasorelaxant activity and in silico insights into eNOS modulation†","authors":"Marian W. Aziz, Khaled O. Mohamed, Amira Karam Khalifa, Doaa B. Farag and Zeinab Mahmoud","doi":"10.1039/D4MD00998C","DOIUrl":"10.1039/D4MD00998C","url":null,"abstract":"<p >Two new series of pyridazin-3-one tethered 4-substituted thiosemicarbazide side chains (<strong>4a–l</strong>) and their cyclized versions (<strong>5a–h</strong>) were designed. The vasorelaxant activities of the newly synthesized compounds were screened using both <em>in vitro</em> and <em>in silico</em> evaluation approaches. The target compounds were synthesized starting from their corresponding 4-substitutedacetophenones and were unambiguously characterized using various spectroscopic techniques. Then, 3D QSAR pharmacophore and molecular docking studies were performed to evaluate the potential activity of the target compounds as well as their binding affinities toward various binding sites of the hypothesized biological receptor (IP3). Subsequently, the synthesized derivatives were assessed for their <em>in vitro</em> vasorelaxant activities over isolated pre-contracted rat thoracic aorta. All synthesized compounds exhibited a potent range of activity, with EC<small>₅₀</small> of 0.0117–2.2680 μM for series <strong>4a–l</strong> and 0.0025–2.9480 μM for series <strong>5a–l</strong> compared with those of the reference standards (EC<small>₅₀</small> of hydralazine, isosorbide mononitrile, diazoxide and nitroglycerin = 18.2100, 30.1, 19.5 and 0.1824, respectively). Compounds <strong>4f</strong>, <strong>4h</strong>, <strong>5d</strong> and <strong>5e</strong> showed superior activity with EC<small>₅₀</small> of 0.0136, 0.0117, 0.0053 and 0.0025 μM, respectively. These compounds demonstrated a remarkable increase in eNOS mRNA expression by approximately 25%, 54.9%, 83.6% and 140.3%, respectively. Moreover, these compounds exhibited a considerable uplevelling of the aortic content of NO by approximately 35.7%, 84%, 135.7% and 186.5%, respectively, compared with the corresponding value in nitroglycerin (<em>P</em> &lt; 0.0001). The computer-based ADMET studies of the new derivatives demonstrated promising physicochemical properties and drug-likeliness behavior, including optimal aqueous solubility, good oral bioavailability, excellent intestinal absorption and no cytochrome <em>P450</em> enzyme inhibition.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4220-4238"},"PeriodicalIF":3.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of hydrazine-based small molecules as metal chelators for KDM4 inhibition†","authors":"Angus J. Saxton, Jayden Sterling, Michael P. Hamilton, Ramzi H. Abbassi, Adam McCluskey, Lenka Munoz and Jennifer R. Baker","doi":"10.1039/D4MD00305E","DOIUrl":"10.1039/D4MD00305E","url":null,"abstract":"<p >Hydrazines and related moieties are frequently employed in inhibitory compounds targeting iron-dependent dioxygenases such as the histone lysine demethylases (KDMs), which are promising targets in targeted epigenetic cancer therapies. Four compound libraries consisting of 81 compounds were synthesized and screened for inhibitory activity against KDM4A in an optimised AlphaScreen assay. Slight inhibition was observed for the series of 3-((2-benzoylhydrazono)methyl)benzoic acids that constituted library 1, with compounds <strong>16</strong>, <strong>17</strong>, <strong>24</strong>, <strong>28</strong>, and <strong>38</strong> exhibiting the most significant reductions in KDM4A activity at a screening concentration of 20 μM. Removal of the hydrazide carbonyl to generate a series of 3-((2-hydrazono)methyl)benzoic acids in library 2 proved detrimental to inhibitory activity except for compound <strong>46</strong>. Evaluation of a series of 2-((2-benzoylhydrazono)methyl)benzoic acids and 2-((2-hydrazono)methyl)benzoic acids in library 3 revealed varied trends compared to matched library 1 and 2 counterparts, however, generally poor activity was observed for most compounds in this library. Masking of the carboxylic acid moiety with a methyl ester was explored in library 4 and resulted in overall reduced KDM4 inhibition compared to matched free acid counterparts in libraries 1, 2, and 3, however, compounds <strong>70</strong> and <strong>72</strong> exhibited markedly improved inhibitory activity with <strong>72</strong> being the most active analogue reported herein at &lt;40% residual KDM4A activity at a screening concentration of 20 μM. Binding poses generated using MOE indicate effective metal chelation by either the carboxylic acid or hydrazine moiety in these compounds consistent with the observed inhibitory activity.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4091-4105"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering allosterism of an Escherichia coli hexuronate metabolism regulator: UxuR†","authors":"Beatriz C. Almeida, Sean A. Wirt, Kristala L. J. Prather and Alexandra T. P. Carvalho","doi":"10.1039/D5MD00391A","DOIUrl":"10.1039/D5MD00391A","url":null,"abstract":"<p > <small>D</small>-Glucuronate and <small>D</small>-galacturonate can be used by <em>Escherichia coli</em> as sole carbon sources. Their use is triggered by external environmental changes through the rearrangement of bacterial metabolic processes. Transcription factors (TFs), the key elements in tailoring gene regulation, enable environmental change responses by transcribing or repressing a gene depending on bacterial needs. Owing to its complexity, allosteric regulation remains a challenging mechanism to fully characterize. Here, the first steps of allosterism behind one TF in hexuronate metabolism in <em>E. coli</em> were revealed by combining molecular dynamics (MD) simulations, graph theory, and biosensors. Enhanced MD simulations were used to characterize one of the repressors of hexuronate metabolism, UxuR TF, in its free and ligand-bound forms. The <em>in silico</em> results provided residue selections that were tested <em>in vitro</em>. The identified residues can be divided into those that are critical for maintaining protein stability and those that are essential for facilitating allosteric communication from the effector domain to the DNA-binding site. A particularly intriguing discovery was the identification of a variant that could respond to different sugars, enriching our understanding of hexuronate metabolism flexibility. The identification of UxuR variants with altered ligand specificity not only advances our understanding of bacterial metabolism regulation but also opens new avenues for developing antimicrobial strategies targeting hexuronate pathways.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4340-4354"},"PeriodicalIF":3.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-aided repositioning and functional in vitro assessment of novel PAD4 inhibitors†","authors":"Sofía Ruiz-Hernández, Fátima de Lourdes Ochoa-González, Julio E. Castañeda-Delgado, Othir Gidalti Galicia-Cruz, Ricardo Castillo-Velázquez, Mauricio Comas-García, Gildardo Rivera and Edgar E. Lara-Ramírez","doi":"10.1039/D5MD00395D","DOIUrl":"10.1039/D5MD00395D","url":null,"abstract":"<p >Peptidyl arginine deiminase 4 (PAD4) is a protein that catalyzes both normal and abnormal citrullination of interacting protein partners, affecting gene regulation and being associated with diseases such as Alzheimer's, cancer, and rheumatoid arthritis (RA). As a result, PAD4 has emerged as a potential therapeutic target; however, no inhibitors have been approved to date. In this study, the REFRAME and ZINC15 drug databases were virtually screened. The approach used molecular docking and dynamics simulation techniques to identify compounds with high-predicted binding affinity to PAD4 (PDB ID: 4DKT). Selected hits from this virtual screening underwent <em>in vitro</em> assays using fixed concentrations derived from the docking score to evaluate their ability to inhibit PAD4 activity, and their effect on neutrophil extracellular trap (NET) release was assessed using an <em>ex vivo</em> human neutrophil model. Computational analyses identified amodiaquine, folic acid, and pyroxamide as stable PAD4 binders. <em>In vitro</em> inhibition assays revealed that amodiaquine (5.0 μM to 1.0 nM) and pyroxamide (0.1 μM) were more potent inhibitors than the reference PAD4 inhibitor BBCla (8.8 μM), while folic acid showed a non-significant trend toward inhibition. Cytotoxicity assays confirmed that all compounds were non-toxic at the tested concentrations, except for amodiaquine at 50 μM. NETosis assays demonstrated that the three selected compounds altered chromatin decondensation and cellular morphology similarly to BBCla, although not uniformly across all cells. Overall, amodiaquine, folic acid, and pyroxamide were identified as PAD4 inhibitors through combined virtual and experimental approaches, supporting their potential as therapeutic candidates for PAD4-related diseases and warranting further investigation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 4405-4414"},"PeriodicalIF":3.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}