ChemMedChem最新文献_第8页

Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458-Based ST6GAL1 Inhibitors Enhance Membrane Permeability 基于JFD 00458的ST6GAL1抑制剂中磺胺脲类生物异构体增强膜通透性。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-26 DOI: 10.1002/cmdc.70465

Natan Koraj, Sushmaa Dangudubiyyam, Adelyn M. Betances-Mora, Ema Faganeli, Anne Harduin-Lepers, Jesús Angulo, Tan Khanh Nguyen, María Bort-Griñó, Ramon Hurtado-Guerrero, Marko Anderluh

{"title":"Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458-Based ST6GAL1 Inhibitors Enhance Membrane Permeability","authors":"Natan Koraj, Sushmaa Dangudubiyyam, Adelyn M. Betances-Mora, Ema Faganeli, Anne Harduin-Lepers, Jesús Angulo, Tan Khanh Nguyen, María Bort-Griñó, Ramon Hurtado-Guerrero, Marko Anderluh","doi":"10.1002/cmdc.70465","DOIUrl":"10.1002/cmdc.70465","url":null,"abstract":"Sialyltransferases catalyze the transfer of sialic acid to glycoconjugates within the Golgi apparatus, generating cell-surface sialoglycans that regulate cell–cell and immune communication. This process can be modulated by inhibiting α−2,6-sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most β-galactoside ST6GAL1 inhibitors are polar CMP-Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor JFD 00458. Here, we designed JFD 00458 analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic-acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm/s]) = −4.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC50 of 1.9 µM. Microscale thermophoresis confirmed direct ST6GAL1 binding, with similar apparent Kd values of approximately 22–25 µM for JFD 00458 and the optimized sulfonylureas. Saturation transfer difference NMR identified the substituted phenoxy phenyl core as a common ST6GAL1-contacting epitope, while closer contacts from the sulfonylurea-linked aromatic substituents in 6d and 6e were associated with the highest inhibitory potency across the series. These results establish sulfonylureas as membrane-permeable sulfonic-acid bioisosteres and provide a structure–activity framework for further ST6GAL1 inhibitor optimization.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Xanthones and Their Nitrogen and Sulfur Analogs in Alzheimer’s Disease: Recent Progress Toward Multifunctional Therapeutics 阿尔茨海默病中的山酮及其氮和硫类似物：多功能治疗的最新进展。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-26 DOI: 10.1002/cmdc.70453

Daniela Malafaia, Lúcia Melo, Artur M. S. Silva, Hélio M. T. Albuquerque

引用次数: 0

Investigating the Binding Mode of a Naphthol-Based Inhibitor Targeting SARS-CoV-2 Main Protease 针对SARS-CoV-2主蛋白酶的萘酚类抑制剂结合模式的研究

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-26 DOI: 10.1002/cmdc.70448

Ifigeneia Akrani, Haifa El Kilani, Franck Touret, Sophia Kouvali, Veronika Gourni, Aggeliki Tsoka, Joulia K. Tsetis, Constantinos Vorgias, Rolf Hilgenfeld, Ioannis K. Kostakis, Vassilios Myrianthopoulos, Emmanuel Mikros

{"title":"Investigating the Binding Mode of a Naphthol-Based Inhibitor Targeting SARS-CoV-2 Main Protease","authors":"Ifigeneia Akrani, Haifa El Kilani, Franck Touret, Sophia Kouvali, Veronika Gourni, Aggeliki Tsoka, Joulia K. Tsetis, Constantinos Vorgias, Rolf Hilgenfeld, Ioannis K. Kostakis, Vassilios Myrianthopoulos, Emmanuel Mikros","doi":"10.1002/cmdc.70448","DOIUrl":"10.1002/cmdc.70448","url":null,"abstract":"Regardless of the massive global efforts to combat the virus causing SARS-CoV-2 syndrome, the infection remains a substantial health challenge worldwide in the years following 2019. To this direction, targeting the main viral protease Mpro has been proposed as a tractable and particularly promising approach toward developing effective and safe COVID-19 antivirals. By applying an integrated workflow combining a previously developed in silico consensus ranking protocol with two orthogonal in vitro methods, the NCI/DTP repository is screened and the discovery of an original naphthol scaffold with Mpro inhibitory properties is reported. The hit is characterized in terms of structure and binding thermodynamics by combining X-ray crystallography and isothermal titration calorimetry where a binding affinity constant of 1.55 μM is determined. The compound is further evaluated against virus-infected cells, where an EC50 value of 7.23 μM and comparable toxicity with nirmatrelvir are measured. Chemical synthesis is additionally employed to facilitate optimal exploration of the structure–activity relationship landscape regarding the new hit. By integrating computational, biophysical, and enzymatic methods, the suggested approach allows the combination of a structural hypothesis with functional evidence and shows its capacity toward identifying and rationally optimizing structurally original noncovalent Mpro inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13512774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and Synthesis of Combretastatin A4-Chalcone Hybrids as Tubulin Polymerization Inhibitors 康布他汀-查尔酮杂化物微管蛋白聚合抑制剂的设计与合成。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-26 DOI: 10.1002/cmdc.70456

Chetna Jadala, Srinivasa Reddy Telukutla, Ganga Reddy Velma, Sowmya Dastari, Ramya Tokala, Lakshmi Tulasi Naraharisetti, Chandraiah Godugu, Suresh K. Bhargava, Magdalena Plebanski, Nagula Shankaraiah, Ahmed Kamal

{"title":"Design and Synthesis of Combretastatin A4-Chalcone Hybrids as Tubulin Polymerization Inhibitors","authors":"Chetna Jadala, Srinivasa Reddy Telukutla, Ganga Reddy Velma, Sowmya Dastari, Ramya Tokala, Lakshmi Tulasi Naraharisetti, Chandraiah Godugu, Suresh K. Bhargava, Magdalena Plebanski, Nagula Shankaraiah, Ahmed Kamal","doi":"10.1002/cmdc.70456","DOIUrl":"10.1002/cmdc.70456","url":null,"abstract":"A new series of combretastatin A4-chalcone hybrids were designed and synthesized to explore their potential as cytotoxic agents. The compounds were evaluated for cytotoxic activity, tubulin inhibition, and anti-angiogenic properties. The designed hybrids exhibited significant cytotoxic effects across all the tested cancer cell lines. Among them, two compounds, 5d and 5o, exhibited potent cytotoxicity, with IC50 values of 0.02 and 0.03 μM, respectively, against the prostate cancer-3 cell line. Further biological investigations suggested that treatment with 5d and 5o induces apoptosis, as evidenced by Hoechst 33 342 staining, Rhodamine 123 staining, MitoSOX red assays, and cell migration assays. Flow cytometric analysis revealed that both compounds caused dose-dependent G2/M phase cell cycle arrest in PC-3 cells. Their ability to inhibit tubulin polymerization was further confirmed through immunofluorescence assays. Additionally, molecular docking studies provided insights into their interaction profiles at the molecular level. Collectively, these findings highlight 5d and 5o as promising lead molecules with potential for further development in anticancer drug discovery.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823634","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}

引用次数: 0

The Coalescence of a “Happy Accident” and an In Vitro Structure–Activity Panel: Increasing the Potency of a Cyclic Peptide Inhibitor to Thrombosis Initiation “幸福事故”和体外结构-活性小组的结合：增加环肽抑制剂对血栓形成的效力。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70457

Gianna M. Barreto, Breanna Wixted, Christopher M. Kouba, Jacob A. Riordan, Christina Tonks, Ryley David, Alexis L. Oldfield, Austin Lisojo, Danielle A. Guarracino

{"title":"The Coalescence of a “Happy Accident” and an In Vitro Structure–Activity Panel: Increasing the Potency of a Cyclic Peptide Inhibitor to Thrombosis Initiation","authors":"Gianna M. Barreto, Breanna Wixted, Christopher M. Kouba, Jacob A. Riordan, Christina Tonks, Ryley David, Alexis L. Oldfield, Austin Lisojo, Danielle A. Guarracino","doi":"10.1002/cmdc.70457","DOIUrl":"10.1002/cmdc.70457","url":null,"abstract":"Cyclic peptides for novel drug discovery utilize the functional groups recognized by most biological targets but impose physical constraints as a preventative to degradation. Substituting non-natural, aromatic amino acids in cyclic peptide motifs can improve the ability of such peptides to bind to their protein targets and can further prevent instability. Here, we appended our previously described synthetic head-to-tail cyclized peptide with naphthylalanine (Nap) or biphenylalanine (BiPhe) substitutions in one or two positions. Our first-generation inhibitor targeted the protein–protein interaction between von Willebrand factor and collagen, implicated in thrombosis linked to cardiovascular diseases. Through an unplanned modification, we omitted a glycine that usually aids the flexibility of ring closing. Using our previously developed fluorescently linked immunosorbent assay, we saw modest improvements for most of the Nap- or BiPhe-substituted peptides, with the largest changes occurring with the no-glycine compound, yielding an inhibitory concentration of 6.47 μM. An array of stability was obtained for all of the peptides using protease degradation assays; however, every BiPhe- or Nap-substituted peptide showed limited degradation over time. Through a “happy accident,” we discovered a new cyclic peptide scaffold, decreasing flexibility in our head-to-tail ring structure, paving the way for novel, potent, cyclic peptides with therapeutic value against thrombosis.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816843","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}

引用次数: 0

Ionizable Cholesterol-Integrated Lipid Nanoparticles for Efficient siRNA Delivery to Solid Tumors 可电离胆固醇整合脂质纳米颗粒用于siRNA高效递送至实体肿瘤。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70464

Suyoung Kang, Duc-Toan Nguyen, Sangyong Jon

{"title":"Ionizable Cholesterol-Integrated Lipid Nanoparticles for Efficient siRNA Delivery to Solid Tumors","authors":"Suyoung Kang, Duc-Toan Nguyen, Sangyong Jon","doi":"10.1002/cmdc.70464","DOIUrl":"10.1002/cmdc.70464","url":null,"abstract":"Lipid nanoparticles (LNPs) are clinically validated platform for the delivery of small interfering RNA (siRNA) therapeutics. However, conventional LNPs typically consist of multiple lipid components, which complicates formulation optimization and limits compositional flexibility. Furthermore, efficient delivery of siRNA to extrahepatic tissues, including solid tumors, remains a major challenge. To address these limitations, we developed a class of ionizable cholesterol derivatives by conjugating biocompatible dimethylated amino acids to cholesterol through a cleavable linker, thereby integrating the structural role of cholesterol and the pH-responsive ionization of ionizable lipids into a single molecule. Five i-Chol derivatives were synthesized and formulated into LNPs, which demonstrated efficient siRNA encapsulation and delivery in cancer cells. The resulting siRNA@i-Chol LNPs exhibited uniform particle size and near-neutral surface charge, indicating favorable physicochemical properties for systemic administration. Notably, phenylalanine-based cholesterol LNPs (Phe-Chol LNPs) loaded with siRNA targeting kinesin spindle protein (KIF11) achieved the most potent in vitro gene knockdown in PC3 prostate cancer cells and induced significant dose-dependent antitumor activity in a xenograft model without observable systemic toxicity. Collectively, this study establishes a simplified i-Chol LNP platform that maintains high siRNA delivery efficiency to solid tumors and provides a versatile framework for further LNP engineering and scalable manufacturing.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816901","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}

引用次数: 0

Design, Synthesis, and Structure–Activity Relationship Studies of Novel 3CLpro Inhibitors 新型3CLpro抑制剂的设计、合成及构效关系研究。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70459

Yixuan Feng, Feng Wang, Donglan Liu, Qiqi Yan, Leyuan Kang, Wenhao Zhao, Shixin Jin, Shuxiang Huang, Jincun Zhao, Ping Tian, Dingding Gao

{"title":"Design, Synthesis, and Structure–Activity Relationship Studies of Novel 3CLpro Inhibitors","authors":"Yixuan Feng, Feng Wang, Donglan Liu, Qiqi Yan, Leyuan Kang, Wenhao Zhao, Shixin Jin, Shuxiang Huang, Jincun Zhao, Ping Tian, Dingding Gao","doi":"10.1002/cmdc.70459","DOIUrl":"10.1002/cmdc.70459","url":null,"abstract":"The SARS-CoV-2 3C-like protease (3CLpro) is an essential enzyme for coronavirus replication and remains an attractive antiviral target due to its high sequence conservation among coronaviruses. Based on a previously identified catechol-containing covalent 3CLpro inhibitor (P1-E11), structural optimization was carried out using a linker-replacement strategy to systematically modify the central linker moiety. Two series comprising 20 analogues were designed, synthesized, and evaluated for enzymatic and antiviral activities. Among them, compound B2, featuring a direct amide linkage between the catechol warhead and the 4-(trifluoromethoxy)phenyl group, exhibited improved enzymatic inhibition (IC50 = 0.83 ± 0.06 μM) and favorable covalent inhibition kinetics (kinact/Ki = 380.01 M−1 s−1). In cell-based assays (A549-hACE2-TMPRSS2), B2 showed antiviral activity (EC50 = 15.03 ± 1.13 μM) with acceptable cytotoxicity (CC50 = 79.87 ± 6.85 μM). Structure–activity relationship analysis revealed that sulfur-containing linkers enhanced antiviral potency in certain cases but were associated with increased cytotoxicity. Collectively, this study expands the structural framework of covalent 3CLpro inhibitors and offers a rational strategy for their further optimization.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816899","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}

引用次数: 0

From Nucleobases to Bioactive NHC-Based Gold and Silver Complexes With Anticancer and Antiviral Activity 从核碱基到具有抗癌和抗病毒活性的生物活性nhc基金银配合物。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70447

Domenico Iacopetta, Jessica Ceramella, Paola Checconi, Flavio Frezza, Maria Marra, Annaluisa Mariconda, Assunta D’Amato, Alessia Catalano, Stefano Aquaro, Pasquale Longo, Maria Stefania Sinicropi

{"title":"From Nucleobases to Bioactive NHC-Based Gold and Silver Complexes With Anticancer and Antiviral Activity","authors":"Domenico Iacopetta, Jessica Ceramella, Paola Checconi, Flavio Frezza, Maria Marra, Annaluisa Mariconda, Assunta D’Amato, Alessia Catalano, Stefano Aquaro, Pasquale Longo, Maria Stefania Sinicropi","doi":"10.1002/cmdc.70447","DOIUrl":"10.1002/cmdc.70447","url":null,"abstract":"N-heterocyclic carbene (NHC) ligands are known for their exceptional versatility and applications, being good σ-donors, sterically tunable and quite stables at different thermic, pH and oxidative conditions. Furthermore, they have been proved to be excellent ligands for transition metals and, particularly, gold (Au) and silver (Ag) complexes have been intensively studied for their biomedical and therapeutic applications. Both NHC-Au- and -Ag complexes have been shown to target selectively cancer cells or bacteria, without exerting side or unwanted effects on the normal cells’ viability. Herein we reported the design, synthesis and biological evaluation of a new series of NHC-Au and -Ag complexes, adopting nucleobases, that is guanine and guanosine, as NHC precursors. The individuated lead, which contains gold, was able to hamper, particularly, the growth of MDA-MB-231 breast cancer cells, inducing genomic DNA damage and apoptosis. Additionally, the same complex exerted an antiviral activity in bronchial epithelial cells infected with influenza virus A/H1N1. The disclosed double biological activity offers new hints in the field of synthesis and pharmaceutical use of biohybrid organometallic complexes, as valid scaffolds for the potential treatment of oncologic patients with viral infection complications or viceversa to hamper the tumor onset after viral infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Iso- and Benzisothiazolinone Inhibitors of Monoacylglycerol Lipase: Exploring On-Target Activity Through Scaffold Decoration and In Situ Warhead Generation 单酰基甘油脂肪酶的异和苯并异噻唑啉酮抑制剂：通过支架修饰和原位弹头生成探索靶向活性。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70414

Edoardo Rocca, Annalida Bedini, Laura Scalvini, Francesca Galvani, Riccardo Castelli, Lorenzo Sarcone, Adriano Recchia, Fabiola Fanini, Adren Tran, Silvia Rivara, Gilberto Spadoni, Daniele Piomelli, Marco Mor

{"title":"Iso- and Benzisothiazolinone Inhibitors of Monoacylglycerol Lipase: Exploring On-Target Activity Through Scaffold Decoration and In Situ Warhead Generation","authors":"Edoardo Rocca, Annalida Bedini, Laura Scalvini, Francesca Galvani, Riccardo Castelli, Lorenzo Sarcone, Adriano Recchia, Fabiola Fanini, Adren Tran, Silvia Rivara, Gilberto Spadoni, Daniele Piomelli, Marco Mor","doi":"10.1002/cmdc.70414","DOIUrl":"10.1002/cmdc.70414","url":null,"abstract":"Monoacylglycerol lipase (MGL) is an intracellular serine hydrolase that regulates endocannabinoid signaling by hydrolyzing 2-arachidonoylglycerol (2-AG), thereby controlling cannabinoid receptor activity and related physiological processes. Targeting MGL through allosteric mechanisms is a promising strategy to modulate 2-AG levels while avoiding limitations associated with active site–directed inhibitors. In this study, we aimed to develop selective MGL inhibitors based on isothiazolinone (ITZ) and benzisothiazolinone (BTZ) scaffolds that covalently target the regulatory cysteine residues Cys201 and Cys208 forming disulfide adducts. Two complementary approaches were explored. First, a mechanism-based strategy was designed to exploit MGL-mediated hydrolysis of O-substituted (benz)isothiazol-3-ol derivatives, enabling localized release of the reactive warhead in proximity to the target cysteines. Second, to enhance molecular recognition, tailored substituents were introduced on the BTZ scaffold to promote selective interactions with residues surrounding the allosteric site. Although several compounds displayed nanomolar inhibitory activity, structure–activity relationship analysis indicated that inhibitory potency is primarily driven by intrinsic warhead reactivity rather than specific protein–ligand interactions. Overall, these findings highlight both the potential and the challenges of developing selective covalent allosteric MGL inhibitors, emphasizing the need for strategies that better balance reactivity and molecular recognition.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Not Quite Folded: Challenges in Predicting the hNPS-hNPSR-Ile107 Complex With AlphaFold2 Multimer 未完全折叠：用AlphaFold2 multitimer预测hNPS-hNPSR-Ile107复合体的挑战。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-08-25 DOI: 10.1002/cmdc.70449

Valentina Albanese, Michela Argentieri, Federica Agosta, Alessandra Rizzo, Delia Preti, Rainer K. Reinscheid, Girolamo Calò, Remo Guerrini, Alfonso Carotenuto, Salvatore Pacifico, Chiara Ruzza, Antonella Ciancetta

{"title":"Not Quite Folded: Challenges in Predicting the hNPS-hNPSR-Ile107 Complex With AlphaFold2 Multimer","authors":"Valentina Albanese, Michela Argentieri, Federica Agosta, Alessandra Rizzo, Delia Preti, Rainer K. Reinscheid, Girolamo Calò, Remo Guerrini, Alfonso Carotenuto, Salvatore Pacifico, Chiara Ruzza, Antonella Ciancetta","doi":"10.1002/cmdc.70449","DOIUrl":"10.1002/cmdc.70449","url":null,"abstract":"The human neuropeptide S (NPS) receptor (NPSR) is a Class A peptide G protein-coupled receptor expressed in the central nervous system and endogenously activated by NPS, a 20-mer peptide. NPSR activation promotes cellular excitability via Gq and Gs signalling. Studies suggest that receptor antagonists may reduce drug-seeking behaviours, whilst agonists represent innovative non-sedating anxiolytics with memory-enhancing effects. Despite its therapeutic potential, NPSR remains poorly characterised, with neither experimental receptor structures nor drug-like clinical candidates available. To fill this gap, we applied a previously validated AlphaFold2 Multimer-based protocol to model the hNPS–hNPSR complex. The model showing higher stability in molecular dynamics simulations and consistency with known structure–activity relationships served as template to design novel hNPS analogues. However, experimental validation through synthesis and in vitro pharmacological evaluation of 20 novel truncated cyclic peptides revealed the model's inability to capture hNPS bioactive conformation, as most analogues were inactive as agonists. By exploiting the stereochemical switch in hNPS hinge region, we identified four novel cyclic antagonists (17–20, pA2 in the 6.10–6.20 range). Our findings highlight strengths and limitations of current peptide-GPCR modelling strategies and underscore the need for integrating AI predictions with experimental refinement to advance ligand discovery for challenging targets like NPSR.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 16","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13507374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0