Pub Date : 2026-01-26DOI: 10.1016/j.bioorg.2026.109538
Xin Zhou , Qi Qin , Huizhi Yao , Yuxing Fu , Linxiao Wang , Wufu Zhu , Qiaoli Lv
Ataxia Telangiectasia and Rad3-related (ATR) kinase is a central orchestrator of the DNA replication stress response and a primary target for exploiting synthetic lethality in DDR-deficient cancers. This review systematically explores the molecular biology of ATR and the medicinal chemistry evolution of its inhibitors. We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Furthermore, we critically examine the pharmacological limitations and developability hurdles associated with Proteolysis-Targeting Chimeras (PROTACs), while evaluating the progress of rational combination regimens in clinical trials. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.
{"title":"ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality—A paradigm shift in Cancer therapy","authors":"Xin Zhou , Qi Qin , Huizhi Yao , Yuxing Fu , Linxiao Wang , Wufu Zhu , Qiaoli Lv","doi":"10.1016/j.bioorg.2026.109538","DOIUrl":"10.1016/j.bioorg.2026.109538","url":null,"abstract":"<div><div>Ataxia Telangiectasia and Rad3-related (ATR) kinase is a central orchestrator of the DNA replication stress response and a primary target for exploiting synthetic lethality in DDR-deficient cancers. This review systematically explores the molecular biology of ATR and the medicinal chemistry evolution of its inhibitors. We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Furthermore, we critically examine the pharmacological limitations and developability hurdles associated with Proteolysis-Targeting Chimeras (PROTACs), while evaluating the progress of rational combination regimens in clinical trials. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109538"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076748","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 : 2026-01-26DOI: 10.1016/j.bioorg.2026.109543
Hongyue Wei , Bing Liu , Ting Zhu , Yuchen Liu , Lijing Zhang , Ning Chen , Wenlan Li
Chiral compounds are highly valuable in pharmaceuticals and materials because of their distinct stereostructures. However, traditional synthesis methods often encounter difficulties, such as demanding reaction conditions and substantial pollution. Biosynthetic technologies, harnessing the intrinsic features of enzymatic catalysis—such as high stereoselectivity and environmental benignity—have established themselves as a pivotal strategy to surmount these traditional limitations. This article reviews recent advances in biocatalytic synthesis of chiral compounds. Key developments include enzyme engineering for precise chiral center formation—through modification of oxidoreductases and lyases, and design of bifunctional and artificial enzymes—as well as photo- and electro-enzymatic catalysis that merge energy-driven processes with biocatalysis for efficient synthesis under mild conditions. Microbial engineering using engineered Escherichia. coli and yeast enables scalable production of chiral compounds, including chiral sesquiterpenes (e.g., (-)-β-elemene, drimenol, albicanol), chiral alkaloid precursors (e.g., (-)-dehydrobrevianamide E), and other high-value chiral intermediates, via optimized metabolic pathways. Mechanistic studies on imine reductases and amino acid dehydrogenases support rational enzyme design. Current technologies exhibit green characteristics, yet confront challenges such as enzyme stability. Looking ahead, the integration of interdisciplinary technologies is expected to drive the intellectualization and sustainability of chiral synthesis technologies.
{"title":"Advances in green technologies for biocatalytic synthesis of chiral compounds: from enzymatic catalysis to multidisciplinary collaborative innovation","authors":"Hongyue Wei , Bing Liu , Ting Zhu , Yuchen Liu , Lijing Zhang , Ning Chen , Wenlan Li","doi":"10.1016/j.bioorg.2026.109543","DOIUrl":"10.1016/j.bioorg.2026.109543","url":null,"abstract":"<div><div>Chiral compounds are highly valuable in pharmaceuticals and materials because of their distinct stereostructures. However, traditional synthesis methods often encounter difficulties, such as demanding reaction conditions and substantial pollution. Biosynthetic technologies, harnessing the intrinsic features of enzymatic catalysis—such as high stereoselectivity and environmental benignity—have established themselves as a pivotal strategy to surmount these traditional limitations. This article reviews recent advances in biocatalytic synthesis of chiral compounds. Key developments include enzyme engineering for precise chiral center formation—through modification of oxidoreductases and lyases, and design of bifunctional and artificial enzymes—as well as photo- and electro-enzymatic catalysis that merge energy-driven processes with biocatalysis for efficient synthesis under mild conditions. Microbial engineering using engineered <em>Escherichia. coli</em> and yeast enables scalable production of chiral compounds, including chiral sesquiterpenes (e.g., (-)-β-elemene, drimenol, albicanol), chiral alkaloid precursors (e.g., (-)-dehydrobrevianamide E), and other high-value chiral intermediates, via optimized metabolic pathways. Mechanistic studies on imine reductases and amino acid dehydrogenases support rational enzyme design. Current technologies exhibit green characteristics, yet confront challenges such as enzyme stability. Looking ahead, the integration of interdisciplinary technologies is expected to drive the intellectualization and sustainability of chiral synthesis technologies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109543"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076749","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 : 2026-01-26DOI: 10.1016/j.bioorg.2026.109563
Huma Basheer , Chandra S. Azad , M. Samim , Imran A. Khan
Cholera toxin B subunit (CTB) is a validated target for anticholera therapeutics, but current inhibitors often suffer from synthetic complexity and limited tunability. This study aimed to develop a compact, tunable triazole scaffold exhibiting low-micromolar potency combined with high synthetic tractability. We applied a unified, QSAR-driven, multiscale computational-experimental workflow integrating molecular docking, induced fit docking (IFD), molecular dynamics (MD), QM/MM calculations, and descriptor-based QSAR modeling to prioritize a focused library of 44 N-sulfonyl triazole inhibitors.
QSAR modeling employed multiple regression techniques on molecular descriptors derived from E-Dragon software and quantum mechanical (QM/QM-MM) parameters. Models including Ordinary Linear Regression, LASSO, Ridge, Elastic Net, Random Forest, Support Vector Machine (SVM), and Gradient Boosting Machine (GBM) were developed. The best predictive performance was achieved by SVM (test R2 = 0.79, RMSE = 0.49) and Random Forest (test R2 = 0.77, RMSE = 0.52) on E-Dragon descriptors, while multiple linear regression yielded outstanding fits on QM descriptors (test R2 up to 0.98, RMSE ∼0.14). Key molecular descriptors influencing activity included hydrogen bond donor count (ndonr), polarizability (AlogP), and topological indices (Jhetv).
Guided by these QSAR models, lead candidates were synthesized via regioselective Cu(I)/Ru-catalyzed click chemistry, with experimental CTB-ELISA screening confirming compound 5d as the most potent inhibitor (IC₅₀ = 11.78 ± 1.2 μM). Computational studies consistently supported these findings, demonstrating favorable binding energetics, dynamic adaptability, and optimal electronic complementarity for lead compounds.
This integrated strategy not only delivers a potent, synthetically accessible monovalent CTB inhibitor but also provides a rational, data-driven platform for rapid design and optimization for multivalent cholera toxin antagonists with improved efficacy.
{"title":"Tunable triazole-based cholera toxin inhibitors: A QSAR-guided design and evaluation approach","authors":"Huma Basheer , Chandra S. Azad , M. Samim , Imran A. Khan","doi":"10.1016/j.bioorg.2026.109563","DOIUrl":"10.1016/j.bioorg.2026.109563","url":null,"abstract":"<div><div>Cholera toxin B subunit (CTB) is a validated target for anticholera therapeutics, but current inhibitors often suffer from synthetic complexity and limited tunability. This study aimed to develop a compact, tunable triazole scaffold exhibiting low-micromolar potency combined with high synthetic tractability. We applied a unified, QSAR-driven, multiscale computational-experimental workflow integrating molecular docking, induced fit docking (IFD), molecular dynamics (MD), QM/MM calculations, and descriptor-based QSAR modeling to prioritize a focused library of 44 N-sulfonyl triazole inhibitors.</div><div>QSAR modeling employed multiple regression techniques on molecular descriptors derived from <em>E</em>-Dragon software and quantum mechanical (QM/QM-MM) parameters. Models including Ordinary Linear Regression, LASSO, Ridge, Elastic Net, Random Forest, Support Vector Machine (SVM), and Gradient Boosting Machine (GBM) were developed. The best predictive performance was achieved by SVM (test R<sup>2</sup> = 0.79, RMSE = 0.49) and Random Forest (test R<sup>2</sup> = 0.77, RMSE = 0.52) on <em>E</em>-Dragon descriptors, while multiple linear regression yielded outstanding fits on QM descriptors (test R<sup>2</sup> up to 0.98, RMSE ∼0.14). Key molecular descriptors influencing activity included hydrogen bond donor count (ndonr), polarizability (AlogP), and topological indices (Jhetv).</div><div>Guided by these QSAR models, lead candidates were synthesized <em>via</em> regioselective Cu(I)/Ru-catalyzed click chemistry, with experimental CTB-ELISA screening confirming compound <strong>5d</strong> as the most potent inhibitor (IC₅₀ = 11.78 ± 1.2 μM). Computational studies consistently supported these findings, demonstrating favorable binding energetics, dynamic adaptability, and optimal electronic complementarity for lead compounds.</div><div>This integrated strategy not only delivers a potent, synthetically accessible monovalent CTB inhibitor but also provides a rational, data-driven platform for rapid design and optimization for multivalent cholera toxin antagonists with improved efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109563"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076812","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 : 2026-01-26DOI: 10.1016/j.bioorg.2026.109561
Esraa Z. Mohammed , Heba S. Rateb , Amira A. Helwa , Nourhan G. Naga , Mona E.M. Mabrouk , Ahmed B.M. Mehany , Hatem A. Abdel Aziz , Nehad M. El-Dydamony
The rapid emergence of antibiotic-resistant pathogens highlights the crucial need for alternate anti-infective strategies. Quorum sensing inhibition (QSI) offers compelling approaches to attenuate bacterial virulence while limiting the resistance. In this study, fourteen Benzo[d]imidazole derivatives were synthesized and proposed as potential LasR antagonists exhibiting quorum-sensing inhibitory activity. Among these, compounds 7f, 7h, 11b, 11c, and 11f demonstrated a marked ability to suppress biofilm formation in P. aeruginosa by (83%, 87%, 84%, 87%, 86%), pyocyanin production (76%, 84%, 86%, 82%, 81%), and motility activity; swimming (90%, 86%, 91%, 88%, 90%), twitching (90%, 94%, 93%, 86%, 92%), respectively. Additionally, compounds 7f and 11c effectively inhibited LasR, with IC50 values equal to 0.74 ± 0.005, 0.79 ± 0.001 μM, respectively. Moreover, a 200-ns molecular dynamics simulation (MDS) of the 7f analogue indicated its potential to disrupt the dimeric structure of the LasR protein, thereby confirming its inhibitory activity toward LasR. Collectively, these results establish benzo[d]imidazole scaffolds as promising leads for the development of next-generation quorum sensing modulators aimed at disarming bacterial pathogenicity and countering antimicrobial resistance.
{"title":"Design, regioselective, time gated synthesis of novel benzo[d]imidazole analogues as potential quorum sensing inhibitors targeting LasR in Pseudomonas aeruginosa","authors":"Esraa Z. Mohammed , Heba S. Rateb , Amira A. Helwa , Nourhan G. Naga , Mona E.M. Mabrouk , Ahmed B.M. Mehany , Hatem A. Abdel Aziz , Nehad M. El-Dydamony","doi":"10.1016/j.bioorg.2026.109561","DOIUrl":"10.1016/j.bioorg.2026.109561","url":null,"abstract":"<div><div>The rapid emergence of antibiotic-resistant pathogens highlights the crucial need for alternate anti-infective strategies. Quorum sensing inhibition (QSI) offers compelling approaches to attenuate bacterial virulence while limiting the resistance. In this study, fourteen <strong>Benzo[<em>d</em>]imidazole</strong> derivatives were synthesized and proposed as potential LasR antagonists exhibiting quorum-sensing inhibitory activity. Among these, compounds <strong>7f</strong>, <strong>7</strong> <strong>h</strong>, <strong>11b, 11c</strong>, and <strong>11f</strong> demonstrated a marked ability to suppress biofilm formation in <em>P. aeruginosa</em> by (83%, 87%, 84%, 87%, 86%), pyocyanin production (76%, 84%, 86%, 82%, 81%), and motility activity; swimming (90%, 86%, 91%, 88%, 90%), twitching (90%, 94%, 93%, 86%, 92%), respectively. Additionally, compounds <strong>7f</strong> and <strong>11c</strong> effectively inhibited LasR, with IC<sub>50</sub> values equal to 0.74 ± 0.005, 0.79 ± 0.001 μM, respectively. Moreover, a 200-ns molecular dynamics simulation (MDS) of the <strong>7f</strong> analogue indicated its potential to disrupt the dimeric structure of the LasR protein, thereby confirming its inhibitory activity toward LasR. Collectively, these results establish <strong>benzo[<em>d</em>]imidazole</strong> scaffolds as promising leads for the development of next-generation quorum sensing modulators aimed at disarming bacterial pathogenicity and countering antimicrobial resistance.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109561"},"PeriodicalIF":4.7,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057332","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 : 2026-01-25DOI: 10.1016/j.bioorg.2026.109546
Ya-Lan Wang , Wen-Zhe Nie , Feng-Zhi Lu , Jin-Ying Liu , Ji-Hang He , Ya-Mei Li , Xiaoting Li , Qing-Kun Shen
PARPi exerts synthetic lethality by exploiting homologous recombination repair (HRR) deficiencies in tumor cells, demonstrating breakthrough efficacy in the treatment of various cancers with BRCA mutations, and has thus become one of the cornerstone strategies in precision oncology. However, primary insensitivity and acquired resistance observed in clinical practice significantly limit its long-term therapeutic benefits. Cyclin-dependent kinases (CDKs), as critical regulators of cell cycle progression and DNA damage repair pathways, represent promising therapeutic targets for overcoming PARPi resistance and enhancing treatment sensitivity. Through modulation of HRR-related gene transcription, activation of cell cycle checkpoints, and regulation of pro-survival signaling pathways in tumors, CDKs play a pivotal role in mediating these effects.This article systematically reviews the core mechanisms underlying the synergistic interaction between CDK inhibitors (CDKi) and PARPi. From a translational perspective, multiple clinical trials have confirmed the safety and preliminary efficacy of this combination strategy in solid tumors, particularly demonstrating synergistic antitumor activity in settings of PARPi resistance or in tumors with intact HRR function. The combinatorial approach of CDKi and PARPi, through multi-dimensional mechanistic integration, holds strong potential as a key strategy to overcome PARPi resistance and expand the population of patients who can benefit from this class of therapies.
{"title":"Is it feasible for CDKs inhibitors to herald a new era in tackling the low sensitivity and drug resistance associated with PARP inhibitors?","authors":"Ya-Lan Wang , Wen-Zhe Nie , Feng-Zhi Lu , Jin-Ying Liu , Ji-Hang He , Ya-Mei Li , Xiaoting Li , Qing-Kun Shen","doi":"10.1016/j.bioorg.2026.109546","DOIUrl":"10.1016/j.bioorg.2026.109546","url":null,"abstract":"<div><div>PARPi exerts synthetic lethality by exploiting homologous recombination repair (HRR) deficiencies in tumor cells, demonstrating breakthrough efficacy in the treatment of various cancers with BRCA mutations, and has thus become one of the cornerstone strategies in precision oncology. However, primary insensitivity and acquired resistance observed in clinical practice significantly limit its long-term therapeutic benefits. Cyclin-dependent kinases (CDKs), as critical regulators of cell cycle progression and DNA damage repair pathways, represent promising therapeutic targets for overcoming PARPi resistance and enhancing treatment sensitivity. Through modulation of HRR-related gene transcription, activation of cell cycle checkpoints, and regulation of pro-survival signaling pathways in tumors, CDKs play a pivotal role in mediating these effects.This article systematically reviews the core mechanisms underlying the synergistic interaction between CDK inhibitors (CDKi) and PARPi. From a translational perspective, multiple clinical trials have confirmed the safety and preliminary efficacy of this combination strategy in solid tumors, particularly demonstrating synergistic antitumor activity in settings of PARPi resistance or in tumors with intact HRR function. The combinatorial approach of CDKi and PARPi, through multi-dimensional mechanistic integration, holds strong potential as a key strategy to overcome PARPi resistance and expand the population of patients who can benefit from this class of therapies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109546"},"PeriodicalIF":4.7,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098619","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 : 2026-01-24DOI: 10.1016/j.bioorg.2026.109560
Xixi Hou , Han Wang , Dong Yan , Baoyu He , Jingjing Guo , Jianxue Yang , Ling Liu
Leveraging febuxostat's liver-targeting properties and the pharmacological versatility of the 1,2,3-triazole scaffold, we designed and synthesized a series of novel febuxostat-linked 1,2,3-triazole derivatives and systematically evaluated their anticancer activity against HepG2 hepatocellular carcinoma cells. Structure–activity relationship analysis revealed that para-substitution of the triazole on the phenyl ring, particularly when combined with a fluorine atom on the benzyl group, markedly enhanced cytotoxicity, with compounds 10c, 10f, and 10 h reducing HepG2 cell viability below 50%. Among these, compound 10 h demonstrated the most potent antiproliferative effect (IC50 = 4.05 ± 0.67 μM), significantly outperforming the reference drug 5-fluorouracil (IC50 = 17.43 ± 4.66 μM), while exhibiting minimal toxicity toward normal liver L02 cells (IC50 > 40 μM). Mechanistic studies revealed that 10 h induced DNA damage and replication stress, as evidenced by increased p-H2AX and S-phase accumulation, accompanied by decreased total levels of PARP-1, caspase-9, and caspase-3, indicating activation of the intrinsic apoptotic pathway. Molecular docking suggested that 10 h binds strongly to human topoisomerase IIα (docking score − 8.341 vs −6.871 for meta-substituted 12 h), supporting a mechanism involving direct enzyme interaction. In vivo, 10 h significantly suppressed tumor growth in a HepG2 xenograft model without overt toxicity. Collectively, these findings establish 10 h as a highly potent and selective anticancer lead compound, acting via DNA damage-induced S-phase arrest and mitochondrial-mediated apoptosis, and highlight its potential for further development as a liver cancer therapeutic.
{"title":"Structure-activity relationship and anticancer mechanism of febuxostat-1,2,3-triazole hybrids inducing DNA damage and apoptosis","authors":"Xixi Hou , Han Wang , Dong Yan , Baoyu He , Jingjing Guo , Jianxue Yang , Ling Liu","doi":"10.1016/j.bioorg.2026.109560","DOIUrl":"10.1016/j.bioorg.2026.109560","url":null,"abstract":"<div><div>Leveraging febuxostat's liver-targeting properties and the pharmacological versatility of the 1,2,3-triazole scaffold, we designed and synthesized a series of novel febuxostat-linked 1,2,3-triazole derivatives and systematically evaluated their anticancer activity against HepG2 hepatocellular carcinoma cells. Structure–activity relationship analysis revealed that para-substitution of the triazole on the phenyl ring, particularly when combined with a fluorine atom on the benzyl group, markedly enhanced cytotoxicity, with compounds 10c, 10f, and 10 h reducing HepG2 cell viability below 50%. Among these, compound 10 h demonstrated the most potent antiproliferative effect (IC<sub>50</sub> = 4.05 ± 0.67 μM), significantly outperforming the reference drug 5-fluorouracil (IC<sub>50</sub> = 17.43 ± 4.66 μM), while exhibiting minimal toxicity toward normal liver L02 cells (IC<sub>50</sub> > 40 μM). Mechanistic studies revealed that 10 h induced DNA damage and replication stress, as evidenced by increased p-H2AX and S-phase accumulation, accompanied by decreased total levels of PARP-1, caspase-9, and caspase-3, indicating activation of the intrinsic apoptotic pathway. Molecular docking suggested that 10 h binds strongly to human topoisomerase IIα (docking score − 8.341 <em>vs</em> −6.871 for meta-substituted 12 h), supporting a mechanism involving direct enzyme interaction. <em>In vivo</em>, 10 h significantly suppressed tumor growth in a HepG2 xenograft model without overt toxicity. Collectively, these findings establish 10 h as a highly potent and selective anticancer lead compound, acting <em>via</em> DNA damage-induced S-phase arrest and mitochondrial-mediated apoptosis, and highlight its potential for further development as a liver cancer therapeutic.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109560"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076750","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 : 2026-01-24DOI: 10.1016/j.bioorg.2026.109555
Ngoc Khanh Vu , Ji-Wan Choi , Hoseong Hwang , Hyeon-Seong Lee , Su-Yeon Cho , Keunwan Park , Hak Cheol Kwon , Won Kyu Kim , Yoon-Jae Song , Jaeyoung Kwon
Although highly effective direct-acting antivirals are available, hepatitis C virus (HCV) infection remains a major global health challenge, causing approximately 200,000 deaths annually, thereby highlighting the need for alternative therapeutic strategies. In this study, extracts of Iris odaesanensis, a plant endemic to Korea, suppressed HCV replication, with the butanol fraction exhibiting particularly potent activity. Molecular networking analysis identified xanthones as the major constituents responsible for this effect. Bioactivity-guided isolation led to the characterization of 11 xanthones, including four new compounds, along with three metabolites from other structural classes. Their structures were elucidated through comprehensive spectroscopic analyses. Among them, compounds 7–9 and 14 demonstrated notable anti-HCV activity. Compounds 7 and 8 inhibited viral polyprotein synthesis mediated by the internal ribosome entry site sequence during the post-entry stages of the HCV life cycle. In addition, evolutionary chemical binding similarity model–based target prediction suggested potential protein targets for these compounds. Compounds 9 and 14 inhibited HCV NS3/4A protease activity in enzymatic assays, while molecular docking provided supportive evidence for binding. All four active compounds suppressed NS5B RNA-dependent RNA polymerase activity in vitro, and docking studies suggested stable interactions within the enzyme's active site. Collectively, these findings highlight I. odaesanensis and its components as potential natural resources for developing multitarget anti-HCV agents, with both experimental validation and in silico predictions contributing to the mechanistic understanding.
{"title":"Antiviral constituents of the Korean endemic plant Iris odaesanensis inhibit hepatitis C virus through multiple targets","authors":"Ngoc Khanh Vu , Ji-Wan Choi , Hoseong Hwang , Hyeon-Seong Lee , Su-Yeon Cho , Keunwan Park , Hak Cheol Kwon , Won Kyu Kim , Yoon-Jae Song , Jaeyoung Kwon","doi":"10.1016/j.bioorg.2026.109555","DOIUrl":"10.1016/j.bioorg.2026.109555","url":null,"abstract":"<div><div>Although highly effective direct-acting antivirals are available, hepatitis C virus (HCV) infection remains a major global health challenge, causing approximately 200,000 deaths annually, thereby highlighting the need for alternative therapeutic strategies. In this study, extracts of <em>Iris odaesanensis</em>, a plant endemic to Korea, suppressed HCV replication, with the butanol fraction exhibiting particularly potent activity. Molecular networking analysis identified xanthones as the major constituents responsible for this effect. Bioactivity-guided isolation led to the characterization of 11 xanthones, including four new compounds, along with three metabolites from other structural classes. Their structures were elucidated through comprehensive spectroscopic analyses. Among them, compounds <strong>7</strong>–<strong>9</strong> and <strong>14</strong> demonstrated notable anti-HCV activity. Compounds <strong>7</strong> and <strong>8</strong> inhibited viral polyprotein synthesis mediated by the internal ribosome entry site sequence during the post-entry stages of the HCV life cycle. In addition, evolutionary chemical binding similarity model–based target prediction suggested potential protein targets for these compounds. Compounds <strong>9</strong> and <strong>14</strong> inhibited HCV NS3/4A protease activity in enzymatic assays, while molecular docking provided supportive evidence for binding. All four active compounds suppressed NS5B RNA-dependent RNA polymerase activity in vitro, and docking studies suggested stable interactions within the enzyme's active site. Collectively, these findings highlight <em>I. odaesanensis</em> and its components as potential natural resources for developing multitarget anti-HCV agents, with both experimental validation and in silico predictions contributing to the mechanistic understanding.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109555"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076850","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 : 2026-01-24DOI: 10.1016/j.bioorg.2026.109556
Lu Han, Yao Deng, Ying-Xin He, Si-Ting Li, Lu-Lu Tan, Zhi-Peng Li, Xiao-Ping Liao, Hao Ren, Chaoqun Zhang, Jian Sun
Antimicrobial resistance (AMR) poses a critical public health threat, primarily driven by the misuse and overuse of antimicrobials in both veterinary and public healthcare systems. In the face of accelerating AMR and a dwindling antibiotic pipeline, the strategic deployment of adjuvant therapies presents a promising approach to potentiate current antibiotics and combat resistant pathogens. Herein, we designed a series of sulfur-based cationic polymers polysulfoniums to obtain a potential antimicrobial adjuvant tackling AMR infections. These polysulfoniums presented effective activity against Gram-positive and Gram-negative bacteria with minimum inhibition concentrations (MICs) of 2 μg/mL. Furthermore, polysulfoniums can completely eradicate bacteria under both aerobic and anaerobic conditions within 2 h. In-depth mechanistic studies revealed that polysulfoniums exhibited bactericidal activities by disrupting outer membrane and the redox balance. Moreover, polysulfoniums helped antimicrobial to enter the bacterial cytoplasm, and the combination of 1,10-PS+ with antimicrobial agent including gentamicin, florfenicol, and ciprofloxacin were an efficient approach to eliminate the bacteria and restored the antimicrobial effectiveness. Additionally, the combination of 1,10-PS+ and ciprofloxacin exhibited robust bactericidal effects, effectively reducing Salmonella colonization in vivo. Overall, this research shed new light on polysulfoniums as antibacterial potentiator, offering viable strategies to restore antimicrobial sensitivity and enable environmentally sustainable clinical applications.
{"title":"Self-assembly nanostructured polysulfoniums as antimicrobial potentiator targeted bacterial membrane reversing antimicrobial resistance.","authors":"Lu Han, Yao Deng, Ying-Xin He, Si-Ting Li, Lu-Lu Tan, Zhi-Peng Li, Xiao-Ping Liao, Hao Ren, Chaoqun Zhang, Jian Sun","doi":"10.1016/j.bioorg.2026.109556","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109556","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) poses a critical public health threat, primarily driven by the misuse and overuse of antimicrobials in both veterinary and public healthcare systems. In the face of accelerating AMR and a dwindling antibiotic pipeline, the strategic deployment of adjuvant therapies presents a promising approach to potentiate current antibiotics and combat resistant pathogens. Herein, we designed a series of sulfur-based cationic polymers polysulfoniums to obtain a potential antimicrobial adjuvant tackling AMR infections. These polysulfoniums presented effective activity against Gram-positive and Gram-negative bacteria with minimum inhibition concentrations (MICs) of 2 μg/mL. Furthermore, polysulfoniums can completely eradicate bacteria under both aerobic and anaerobic conditions within 2 h. In-depth mechanistic studies revealed that polysulfoniums exhibited bactericidal activities by disrupting outer membrane and the redox balance. Moreover, polysulfoniums helped antimicrobial to enter the bacterial cytoplasm, and the combination of 1,10-PS+ with antimicrobial agent including gentamicin, florfenicol, and ciprofloxacin were an efficient approach to eliminate the bacteria and restored the antimicrobial effectiveness. Additionally, the combination of 1,10-PS+ and ciprofloxacin exhibited robust bactericidal effects, effectively reducing Salmonella colonization in vivo. Overall, this research shed new light on polysulfoniums as antibacterial potentiator, offering viable strategies to restore antimicrobial sensitivity and enable environmentally sustainable clinical applications.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"109556"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122910","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}
Red sea bream iridovirus (RSIV), a member of the genus Megalocytivirus, poses a substantial threat to global aquaculture through its infection of marine fish species. The major capsid protein (MCP) represents the principal immunogenic component of RSIV, yet the mechanisms governing its pathogenicity is unclear. Here, we employed a comprehensive approach combining protein interaction screening with artificial intelligence-based structural prediction to elucidate the interface between RSIV and its host. In brief, by constructing a yeast cDNA library of membrane protein in red snapper and using a membrane yeast two hybrid system, a cDNA library targeting RSIV-MCP was screened, and 53 different host interaction partners were identified from the preliminary screening of 96 positive clones. Reverse validation confirmed robust protein-protein interactions for all candidates, including heat shock proteins Hsc70, HSP90β, and HSC71-like protein. Leveraging AlphaFold3 for structural prediction, we generated high-confidence models of MCP and HSC70, enabling molecular docking and dynamics simulations. The resulting complex demonstrated structural stability within 100 ns, as reflected by convergence of root-mean-square deviation and radius of gyration values. Computational analyses revealed an extensive hydrogen-bond network at the binding interface. This finding is further supported by a calculated binding free energy of −318.45 kJ/mol, indicating a potentially strong interaction between MCP and HSC70. Mutational analysis identified key residues 646ILE and 452ILE as critical mediators of complex formation, with hydrogen bonding and van der Waals interactions serving as primary stabilizing forces. These results provide insights into RSIV-host protein interactions, establishing a foundation for understanding viral pathogenesis and developing targeted therapeutic strategies against this economically significant aquatic pathogen.
{"title":"Insights into red sea bream iridovirus pathogenesis: Unveiling host-pathogen interactions using membrane yeast two-hybrid and molecular dynamics","authors":"Weichao Chen, Jialong Yu, Meijia He, Hailian Wu, Dekui Qiu, Chao Zhao","doi":"10.1016/j.bioorg.2026.109547","DOIUrl":"10.1016/j.bioorg.2026.109547","url":null,"abstract":"<div><div>Red sea bream iridovirus (RSIV), a member of the genus Megalocytivirus, poses a substantial threat to global aquaculture through its infection of marine fish species. The major capsid protein (MCP) represents the principal immunogenic component of RSIV, yet the mechanisms governing its pathogenicity is unclear. Here, we employed a comprehensive approach combining protein interaction screening with artificial intelligence-based structural prediction to elucidate the interface between RSIV and its host. In brief, by constructing a yeast cDNA library of membrane protein in red snapper and using a membrane yeast two hybrid system, a cDNA library targeting RSIV-MCP was screened, and 53 different host interaction partners were identified from the preliminary screening of 96 positive clones. Reverse validation confirmed robust protein-protein interactions for all candidates, including heat shock proteins Hsc70, HSP90β, and HSC71-like protein. Leveraging AlphaFold3 for structural prediction, we generated high-confidence models of MCP and HSC70, enabling molecular docking and dynamics simulations. The resulting complex demonstrated structural stability within 100 ns, as reflected by convergence of root-mean-square deviation and radius of gyration values. Computational analyses revealed an extensive hydrogen-bond network at the binding interface. This finding is further supported by a calculated binding free energy of −318.45 kJ/mol, indicating a potentially strong interaction between MCP and HSC70. Mutational analysis identified key residues 646ILE and 452ILE as critical mediators of complex formation, with hydrogen bonding and van der Waals interactions serving as primary stabilizing forces. These results provide insights into RSIV-host protein interactions, establishing a foundation for understanding viral pathogenesis and developing targeted therapeutic strategies against this economically significant aquatic pathogen.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109547"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073895","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 : 2026-01-24DOI: 10.1016/j.bioorg.2026.109540
Shakir Ahamad , Parameswari Akshinthala , Faaizah Fazal , Gautam Kumar Sah , Mobashshir Hasan Khan , Akanksha Upadhyay , Shahnawaz Ali Bhat , Mohd Kamil Hussain
The Wnt/β-catenin pathway regulates key processes such as neurogenesis, synaptic plasticity, and neuroinflammation, each disrupted in neurodegenerative disorders like AD, PD, ALS, and stroke. Small molecules have shown potential to restore this signaling axis and confer neuroprotection. While these molecules modulate Wnt activity, none has achieved FDA approval, primarily due to poor brain permeability, off-target effects, and insufficient biomarker-based validation. Moreover, current strategies remain disproportionately focused on GSK-3β, with other viable targets, such as DKK1, NOTUM, SFRP-1, sclerostin, and Dvl–CXXC5 or Axin–β-catenin interactions, largely underexplored. Natural products, particularly flavonoids and diterpenoids, offer valuable scaffolds; however, their SAR remain poorly characterized, and promising synthetic leads often lack further development. This review highlights recent pharmacological advances, emerging molecular targets, and key translational barriers. Future success will depend on optimizing pharmacokinetics, improving brain-targeted delivery, and integrating biomarker-driven strategies into clinical trial design.
{"title":"Small-molecule-based activation of Wnt/β-catenin signaling: An underexplored yet promising strategy for neuroprotection","authors":"Shakir Ahamad , Parameswari Akshinthala , Faaizah Fazal , Gautam Kumar Sah , Mobashshir Hasan Khan , Akanksha Upadhyay , Shahnawaz Ali Bhat , Mohd Kamil Hussain","doi":"10.1016/j.bioorg.2026.109540","DOIUrl":"10.1016/j.bioorg.2026.109540","url":null,"abstract":"<div><div>The Wnt/β-catenin pathway regulates key processes such as neurogenesis, synaptic plasticity, and neuroinflammation, each disrupted in neurodegenerative disorders like AD, PD, ALS, and stroke. Small molecules have shown potential to restore this signaling axis and confer neuroprotection. While these molecules modulate Wnt activity, none has achieved FDA approval, primarily due to poor brain permeability, off-target effects, and insufficient biomarker-based validation. Moreover, current strategies remain disproportionately focused on GSK-3β, with other viable targets, such as DKK1, NOTUM, SFRP-1, sclerostin, and Dvl–CXXC5 or Axin–β-catenin interactions, largely underexplored. Natural products, particularly flavonoids and diterpenoids, offer valuable scaffolds; however, their SAR remain poorly characterized, and promising synthetic leads often lack further development. This review highlights recent pharmacological advances, emerging molecular targets, and key translational barriers. Future success will depend on optimizing pharmacokinetics, improving brain-targeted delivery, and integrating biomarker-driven strategies into clinical trial design.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109540"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073898","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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