Pub Date : 2026-03-05Epub Date: 2025-12-16DOI: 10.1016/j.ejmech.2025.118476
Sharad Kumar Suthar , Tamás Jernei , Csilla Kurdi , Ádam I. Horváth , Anna Ágnes Rauscher , Máté Gyimesi , András Málnási-Csizmadia
Smooth muscle myosin-2 (SMM) is a promising target for treating asthma and COPD, but selective inhibition remains challenging due to the high conservation of myosin-2 isoforms. CK-571 is the first potent and selective SMM inhibitor, despite binding to an allosteric site conserved across isoforms. We performed a fragment-based structure–activity relationship analysis to deconstruct CK-571 and define the role of each segment. The isoquinoline-carbamate and chloro-fluorobenzyl moieties were found to be inactive when isolated. Surprisingly, the presence of a methyl group and a solvent-exposed pair of non-interacting dihydroxyl groups dramatically enhanced potency by up to 100-fold, despite no direct contact with the protein. These findings highlight the critical contribution of non-interacting, flexible groups in optimizing ligand potency and selectivity for conserved targets and establish a framework for the development of improved SMM-targeted therapeutics.
{"title":"Fragment-based structure-activity relationship analysis of CK-571 reveals non-interacting groups drive smooth muscle myosin selectivity","authors":"Sharad Kumar Suthar , Tamás Jernei , Csilla Kurdi , Ádam I. Horváth , Anna Ágnes Rauscher , Máté Gyimesi , András Málnási-Csizmadia","doi":"10.1016/j.ejmech.2025.118476","DOIUrl":"10.1016/j.ejmech.2025.118476","url":null,"abstract":"<div><div>Smooth muscle myosin-2 (SMM) is a promising target for treating asthma and COPD, but selective inhibition remains challenging due to the high conservation of myosin-2 isoforms. CK-571 is the first potent and selective SMM inhibitor, despite binding to an allosteric site conserved across isoforms. We performed a fragment-based structure–activity relationship analysis to deconstruct CK-571 and define the role of each segment. The isoquinoline-carbamate and chloro-fluorobenzyl moieties were found to be inactive when isolated. Surprisingly, the presence of a methyl group and a solvent-exposed pair of non-interacting dihydroxyl groups dramatically enhanced potency by up to 100-fold, despite no direct contact with the protein. These findings highlight the critical contribution of non-interacting, flexible groups in optimizing ligand potency and selectivity for conserved targets and establish a framework for the development of improved SMM-targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118476"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785943","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 : 2026-03-05Epub Date: 2026-01-13DOI: 10.1016/j.ejmech.2026.118578
Yichao Kong , Mengjun Su , Caihong Jiang , Haonan Feng , Yingjie Hu , Donglai Li , Zhenyu Mao , Fengling Liu , Fuli Zhu , Yue Guo , Shuhua Ren , Man Chi , Ting Qiu , Yaxia Yuan , Weiwei Huang , Lei Ma , Xiabin Chen
Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of M48, a derivative that exhibited superior anti-inflammatory activity (IC50 = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, M48 demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, M48's enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and other NLRP3-associated diseases.
{"title":"Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy","authors":"Yichao Kong , Mengjun Su , Caihong Jiang , Haonan Feng , Yingjie Hu , Donglai Li , Zhenyu Mao , Fengling Liu , Fuli Zhu , Yue Guo , Shuhua Ren , Man Chi , Ting Qiu , Yaxia Yuan , Weiwei Huang , Lei Ma , Xiabin Chen","doi":"10.1016/j.ejmech.2026.118578","DOIUrl":"10.1016/j.ejmech.2026.118578","url":null,"abstract":"<div><div>Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of <strong>M48</strong>, a derivative that exhibited superior anti-inflammatory activity (IC<sub>50</sub> = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, <strong>M48</strong> demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, <strong>M48</strong>'s enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and other NLRP3-associated diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118578"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962570","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 : 2026-03-05Epub Date: 2026-01-03DOI: 10.1016/j.ejmech.2025.118542
Dongping Yao , Ni Zhang , Qian Yao , Yongmei Xie , Rong Tian , Xiaoai Wu , Weihong Kuang
Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (Ki = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct SNAr radiofluorination, 18F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D7.4 measurement indicated 18F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with 18F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. 18F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of 18F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.
{"title":"Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations","authors":"Dongping Yao , Ni Zhang , Qian Yao , Yongmei Xie , Rong Tian , Xiaoai Wu , Weihong Kuang","doi":"10.1016/j.ejmech.2025.118542","DOIUrl":"10.1016/j.ejmech.2025.118542","url":null,"abstract":"<div><div>Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-<em>a</em>]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound <strong>28</strong>, which showed high affinity with tau aggregates (<em>K</em><sub><em>i</em></sub> = 0.99 nM). Compound <strong>28</strong> also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct S<sub>N</sub>Ar radiofluorination, <sup>18</sup>F-<strong>28</strong> was successfully produced with high radiochemical yield. <em>In vitro</em> stability tests and log <em>D</em><sub><em>7.4</em></sub> measurement indicated <sup>18</sup>F-<strong>28</strong> hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and <em>in vivo</em> PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with <sup>18</sup>F-<strong>28</strong> in normal mice and P301L transgenic mice, as well as a fast clearance from brain. <sup>18</sup>F-<strong>28</strong> was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of <sup>18</sup>F-<strong>28</strong> with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound <strong>28</strong> holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118542"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895253","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 : 2026-03-05Epub Date: 2026-01-09DOI: 10.1016/j.ejmech.2026.118576
François Sindt, Didier Rognan
On-demand chemical spaces consist of molecules that are, a priori, readily synthesizable from sets of commercial building blocks through robust organic reactions. As these spaces expand—now reaching the scale of several trillions of compounds—computational chemists are compelled to develop innovative algorithms for efficient enumeration, storage, and virtual screening, particularly when three-dimensional constraints of target proteins are involved. This review examines the primary approaches to structure-based ultra-large virtual screening, highlighting the significant advantages of screening at such a scale while addressing the remaining practical and theoretical hurdles. Current prospective applications, often relying on brute-force docking, typically report improved hit rates and more potent primary hits; however, they must contend with the exponential growth of available chemical space. To address this, recent developments have integrated active learning, probabilistic sampling, and synthon-guided methods to accelerate docking and prioritize the most promising compounds. Finally, we provide a perspective on the transformative impact of ultra-large chemical spaces on early hit identification and the overall organization of early drug discovery.
{"title":"Structure-based virtual screening of ultra-large chemical spaces: Advances and pitfalls","authors":"François Sindt, Didier Rognan","doi":"10.1016/j.ejmech.2026.118576","DOIUrl":"10.1016/j.ejmech.2026.118576","url":null,"abstract":"<div><div>On-demand chemical spaces consist of molecules that are, <em>a priori</em>, readily synthesizable from sets of commercial building blocks through robust organic reactions. As these spaces expand—now reaching the scale of several trillions of compounds—computational chemists are compelled to develop innovative algorithms for efficient enumeration, storage, and virtual screening, particularly when three-dimensional constraints of target proteins are involved. This review examines the primary approaches to structure-based ultra-large virtual screening, highlighting the significant advantages of screening at such a scale while addressing the remaining practical and theoretical hurdles. Current prospective applications, often relying on brute-force docking, typically report improved hit rates and more potent primary hits; however, they must contend with the exponential growth of available chemical space. To address this, recent developments have integrated active learning, probabilistic sampling, and synthon-guided methods to accelerate docking and prioritize the most promising compounds. Finally, we provide a perspective on the transformative impact of ultra-large chemical spaces on early hit identification and the overall organization of early drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118576"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947734","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 : 2026-03-05Epub Date: 2026-01-12DOI: 10.1016/j.ejmech.2026.118575
Hassan Gamal , Cesar Augusto Roque-Borda , Beatriz G. de la Torre , Fernando Albericio
Polymyxins, particularly colistin, have re-emerged as last-line antibiotics against multidrug-resistant Gram-negative bacteria. Beyond their clinical revival, they represent a unique platform for medicinal chemistry, owing to their cyclic peptide scaffold, cationic diaminobutyric acid residues, and hydrophobic fatty acyl tail. Recent advances in solid-phase synthesis, structural biology, and molecular pharmacology have revealed critical structure–activity relationships (SAR) that govern antibacterial potency, toxicity, and resistance. This review highlights how chemical modification of Dab side chains, the N-terminal fatty acid, and the cyclic heptapeptide ring has led to next-generation analogues with improved efficacy and safety. We further discuss emerging synthetic strategies, mimetic design, and combination therapies that exploit polymyxin scaffolds to overcome resistance. These insights showcase polymyxins not merely as “old drugs” but as versatile chemical blueprints for innovative lipopeptide therapeutics targeting Gram-negative “superbugs”.
{"title":"Structure function and design of polymyxins to enable safer and more potent anti Gram negative agents","authors":"Hassan Gamal , Cesar Augusto Roque-Borda , Beatriz G. de la Torre , Fernando Albericio","doi":"10.1016/j.ejmech.2026.118575","DOIUrl":"10.1016/j.ejmech.2026.118575","url":null,"abstract":"<div><div>Polymyxins, particularly colistin, have re-emerged as last-line antibiotics against multidrug-resistant Gram-negative bacteria. Beyond their clinical revival, they represent a unique platform for medicinal chemistry, owing to their cyclic peptide scaffold, cationic diaminobutyric acid residues, and hydrophobic fatty acyl tail. Recent advances in solid-phase synthesis, structural biology, and molecular pharmacology have revealed critical structure–activity relationships (SAR) that govern antibacterial potency, toxicity, and resistance. This review highlights how chemical modification of Dab side chains, the N-terminal fatty acid, and the cyclic heptapeptide ring has led to next-generation analogues with improved efficacy and safety. We further discuss emerging synthetic strategies, mimetic design, and combination therapies that exploit polymyxin scaffolds to overcome resistance. These insights showcase polymyxins not merely as “old drugs” but as versatile chemical blueprints for innovative lipopeptide therapeutics targeting Gram-negative “superbugs”.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118575"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949946","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 : 2026-03-05Epub Date: 2026-01-09DOI: 10.1016/j.ejmech.2026.118574
Fansheng Ran , Rong Cao , Yifan Ma , Dongliang Ji , Tiantian Sun , Mingming Chang , Chen Chen , Chunyu Yin , Hongming Huang , Yong Ling
The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (6a-6s) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound 6s demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC50) = 14 nM) compared with the reference drug tandutinib (IC50 = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC50 = 27 nM) relative to vorinostat (SAHA; IC50 = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, 6s exhibits remarkable antiproliferative potency (IC50 = 29 nM), outperforming the single-target inhibitors tandutinib (IC50 = 7630 nM) and SAHA (IC50 = 3760 nM) by 263- and 129-folds, respectively. Notably, 6s shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC50 = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, 6s exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, 6s achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that 6s is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.
{"title":"Discovery of novel aminopyrimidine-hydroxamate derivatives as dual FLT3/HDAC inhibitors: Design, synthesis, and anti-hematologic malignancy evaluation","authors":"Fansheng Ran , Rong Cao , Yifan Ma , Dongliang Ji , Tiantian Sun , Mingming Chang , Chen Chen , Chunyu Yin , Hongming Huang , Yong Ling","doi":"10.1016/j.ejmech.2026.118574","DOIUrl":"10.1016/j.ejmech.2026.118574","url":null,"abstract":"<div><div>The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (<strong>6a-6s</strong>) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound <strong>6s</strong> demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC<sub>50</sub>) = 14 nM) compared with the reference drug tandutinib (IC<sub>50</sub> = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC<sub>50</sub> = 27 nM) relative to vorinostat (SAHA; IC<sub>50</sub> = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, <strong>6s</strong> exhibits remarkable antiproliferative potency (IC<sub>50</sub> = 29 nM), outperforming the single-target inhibitors tandutinib (IC<sub>50</sub> = 7630 nM) and SAHA (IC<sub>50</sub> = 3760 nM) by 263- and 129-folds, respectively. Notably, <strong>6s</strong> shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC<sub>50</sub> = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, <strong>6s</strong> exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, <strong>6s</strong> achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that <strong>6s</strong> is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118574"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956887","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 : 2026-03-05Epub Date: 2026-01-07DOI: 10.1016/j.ejmech.2026.118563
Boxiang Qiu , Ruihua Fan , Guangxu Si , Jing Wang , Kailun Wang , Guojun Zheng , Xinxin Tian
Breast cancer is one of the most common malignant tumors among women, with approximately 50–60 % of cases overexpressing the luteinizing hormone-releasing hormone receptor (LHRH-R), making it an important therapeutic target. To overcome the limitations of conventional chemotherapy, this study designed and synthesized a novel LHRH-R-targeting peptide, LHRH-III′, based on the structure of natural LHRH-III with rational structural modifications. Fluorescence labeling experiments demonstrated that this peptide binds to 4T1 cells with an affinity comparable to or superior to that of the classical LHRH-R targeting peptide [D-Lys6]-LHRH-I, while its cellular internalization efficiency was increased by more than 6-fold. Subsequently, LHRH-III′ was conjugated to camptothecin (CPT) or doxorubicin (Dox) via a disulfide bond linker to construct peptide-drug conjugates (PDCs). Among these conjugates, LHRH-III′–SS–CPT exhibited more efficient glutathione (GSH)-responsive drug release than LHRH-III′–SS–Dox. In antitumor evaluations, LHRH-III′–SS–CPT demonstrated significant antitumor activity both in vitro and in vivo. Biodistribution studies revealed that hepatic accumulation of LHRH-III′ was only one-sixth of that observed with the control peptide [D-Lys6]-LHRH-I, substantially reducing the risk of potential hepatotoxicity caused by off-target accumulation. In summary, the novel targeting peptide LHRH-III′ developed in this study exhibits excellent targeting capability for breast cancer. The lead PDC based on LHRH-III′ (LHRH-III′–SS–CPT) demonstrate promising antitumor efficacy and low toxicity, highlighting their potential application value as a targeted therapeutic strategy for breast cancer.
{"title":"A novel luteinizing hormone-releasing hormone (LHRH) receptor-targeting peptide LHRH-III': Design and application for targeted breast cancer therapy","authors":"Boxiang Qiu , Ruihua Fan , Guangxu Si , Jing Wang , Kailun Wang , Guojun Zheng , Xinxin Tian","doi":"10.1016/j.ejmech.2026.118563","DOIUrl":"10.1016/j.ejmech.2026.118563","url":null,"abstract":"<div><div>Breast cancer is one of the most common malignant tumors among women, with approximately 50–60 % of cases overexpressing the luteinizing hormone-releasing hormone receptor (LHRH-R), making it an important therapeutic target. To overcome the limitations of conventional chemotherapy, this study designed and synthesized a novel LHRH-R-targeting peptide, LHRH-III′, based on the structure of natural LHRH-III with rational structural modifications. Fluorescence labeling experiments demonstrated that this peptide binds to 4T1 cells with an affinity comparable to or superior to that of the classical LHRH-R targeting peptide [D-Lys<sup>6</sup>]-LHRH-I, while its cellular internalization efficiency was increased by more than 6-fold. Subsequently, LHRH-III′ was conjugated to camptothecin (CPT) or doxorubicin (Dox) via a disulfide bond linker to construct peptide-drug conjugates (PDCs). Among these conjugates, LHRH-III′–SS–CPT exhibited more efficient glutathione (GSH)-responsive drug release than LHRH-III′–SS–Dox. In antitumor evaluations, LHRH-III′–SS–CPT demonstrated significant antitumor activity both <em>in vitro</em> and <em>in vivo</em>. Biodistribution studies revealed that hepatic accumulation of LHRH-III′ was only one-sixth of that observed with the control peptide [D-Lys<sup>6</sup>]-LHRH-I, substantially reducing the risk of potential hepatotoxicity caused by off-target accumulation. In summary, the novel targeting peptide LHRH-III′ developed in this study exhibits excellent targeting capability for breast cancer. The lead PDC based on LHRH-III′ (LHRH-III′–SS–CPT) demonstrate promising antitumor efficacy and low toxicity, highlighting their potential application value as a targeted therapeutic strategy for breast cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118563"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920573","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}
Small-molecule inhibitors targeting heparin (HP)-protein interactions represent a promising strategy for developing therapeutic agents against serious bleeding complications. Herein, we report a rational design and synthesis of a library of eight trisaccharide HP mimetics incorporating positively charged guanidinium residues aimed at disrupting the ionic interactions of HP and modulating HP-mediated biological activities. The introduction of guanidine residue in HP backbone significantly influenced the conformational plasticity of l-idose and l-iduronic acid, shifting the major 4C1-conformation to predominant 2S0-geometries, akin to the role of high sulfation in native HS. Unlike aminoglycosides, the guanidine-based HP mimetics exhibited no antibacterial activity and demonstrated low cytotoxicity towards both cancerous and normal cell lines. When evaluated as potential antidotes for heparin and fondaparinux-mediated blood coagulation, the highly guanidine-substituted HP mimetics displayed sub-micromolar antagonist potency. NMR studies further confirmed the carbohydrate–carbohydrate interactions between fondaparinux and the HP mimetics, providing a mechanistic basis for the observed activity and introducing a new strategy to block HP-mediated biological functions.
{"title":"Rational design of heparin antagonist: Guanidine-based mimetics unveil key carbohydrate-carbohydrate interactions","authors":"Ankita Chandra , Ana Gimeno , María Payá-García , Preeti Ravindra Bhoge , Virendrasinh Mahida , Jesús Jiménez-Barbero , Raghavendra Kikkeri","doi":"10.1016/j.ejmech.2025.118551","DOIUrl":"10.1016/j.ejmech.2025.118551","url":null,"abstract":"<div><div>Small-molecule inhibitors targeting heparin (HP)-protein interactions represent a promising strategy for developing therapeutic agents against serious bleeding complications. Herein, we report a rational design and synthesis of a library of eight trisaccharide HP mimetics incorporating positively charged guanidinium residues aimed at disrupting the ionic interactions of HP and modulating HP-mediated biological activities. The introduction of guanidine residue in HP backbone significantly influenced the conformational plasticity of <span>l</span>-idose and <span>l</span>-iduronic acid, shifting the major <sup>4</sup>C<sub>1</sub>-conformation to predominant <sup>2</sup>S<sub>0</sub>-geometries, akin to the role of high sulfation in native HS. Unlike aminoglycosides, the guanidine-based HP mimetics exhibited no antibacterial activity and demonstrated low cytotoxicity towards both cancerous and normal cell lines. When evaluated as potential antidotes for heparin and fondaparinux-mediated blood coagulation, the highly guanidine-substituted HP mimetics displayed sub-micromolar antagonist potency. NMR studies further confirmed the carbohydrate–carbohydrate interactions between fondaparinux and the HP mimetics, providing a mechanistic basis for the observed activity and introducing a new strategy to block HP-mediated biological functions.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118551"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895283","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}
A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by in vitro and in vivo methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC50 values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The in vivo FST and TST results corroborated well with the findings from in vitro MAO inhibition. Further, antioxidant properties were assessed using in vitro assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (in silico). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood–brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.
{"title":"Synthesis, antidepressant evaluation and computational insights on substituted pyrazoles as selective MAO-A inhibitors","authors":"Diksha Choudhary , Rajwinder Kaur , Kailash Jangid , Vinod Kumar , Bhupinder Kumar , Thishana Singh , Amritpal Kaur , Shareen Singh , Manjinder Singh , Thakur Gurjeet Singh , Balakumar Chandrasekaran","doi":"10.1016/j.ejmech.2026.118556","DOIUrl":"10.1016/j.ejmech.2026.118556","url":null,"abstract":"<div><div>A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by <em>in vitro</em> and <em>in vivo</em> methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC<sub>50</sub> values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The <em>in vivo</em> FST and TST results corroborated well with the findings from <em>in vitro</em> MAO inhibition. Further, antioxidant properties were assessed using <em>in vitro</em> assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (<em>in silico</em>). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood–brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118556"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895279","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 : 2026-03-05Epub Date: 2025-12-30DOI: 10.1016/j.ejmech.2025.118540
Kyathi Kolli, Dileep Kumar
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense stromal barrier, aggressive invasion, and resistance to therapy. Matrix metalloproteinases (MMPs), zinc-dependent endopeptidases responsible for extracellular matrix remodeling, play a critical role in PDAC progression, metastasis, and tumor microenvironment modulation. Consequently, selective inhibition of MMP isoforms has emerged as a promising therapeutic strategy. Early hydroxamate-based MMP inhibitors demonstrated potent activity but failed clinically due to poor selectivity, zinc chelation-related toxicity, and limited pharmacokinetic profiles. Recent medicinal chemistry efforts have focused on scaffold modification to overcome these challenges, leading to the evolution of alternative zinc-binding groups (ZBGs) such as carboxylates, phosphonates, thiols, and sulfonamides. This review systematically summarizes scaffold optimization trends in MMP inhibitors, correlating structural features with enzyme selectivity and anticancer efficacy. Structure–activity relationship (SAR) studies highlight the role of aromatic and polar substituents in enhancing binding affinity and isoform discrimination. Additionally, computational modeling, pharmacophore mapping, and molecular docking analyses provide mechanistic insights into ligand-enzyme interactions within the catalytic Zn2+ site. The review also discusses crystallographic data and structure-based drug design approaches that guide next-generation MMP inhibitor development. Collectively, this work emphasizes medicinal chemistry strategies for designing potent, selective, and bioavailable MMP inhibitors, thereby advancing rational therapeutic approaches for targeted PDAC management.
{"title":"Scaffold optimization trends in matrix metalloproteinase inhibitors for selective pancreatic cancer Therapy—A review","authors":"Kyathi Kolli, Dileep Kumar","doi":"10.1016/j.ejmech.2025.118540","DOIUrl":"10.1016/j.ejmech.2025.118540","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense stromal barrier, aggressive invasion, and resistance to therapy. Matrix metalloproteinases (MMPs), zinc-dependent endopeptidases responsible for extracellular matrix remodeling, play a critical role in PDAC progression, metastasis, and tumor microenvironment modulation. Consequently, selective inhibition of MMP isoforms has emerged as a promising therapeutic strategy. Early hydroxamate-based MMP inhibitors demonstrated potent activity but failed clinically due to poor selectivity, zinc chelation-related toxicity, and limited pharmacokinetic profiles. Recent medicinal chemistry efforts have focused on scaffold modification to overcome these challenges, leading to the evolution of alternative zinc-binding groups (ZBGs) such as carboxylates, phosphonates, thiols, and sulfonamides. This review systematically summarizes scaffold optimization trends in MMP inhibitors, correlating structural features with enzyme selectivity and anticancer efficacy. Structure–activity relationship (SAR) studies highlight the role of aromatic and polar substituents in enhancing binding affinity and isoform discrimination. Additionally, computational modeling, pharmacophore mapping, and molecular docking analyses provide mechanistic insights into ligand-enzyme interactions within the catalytic Zn<sup>2+</sup> site. The review also discusses crystallographic data and structure-based drug design approaches that guide next-generation MMP inhibitor development. Collectively, this work emphasizes medicinal chemistry strategies for designing potent, selective, and bioavailable MMP inhibitors, thereby advancing rational therapeutic approaches for targeted PDAC management.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"305 ","pages":"Article 118540"},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895304","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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