Journal of Medicinal Chemistry最新文献_第2页

What, This "Base" Is Not a Base? Common Misconceptions about Aqueous Ionization That May Hinder Drug Discovery and Development. 什么，这个“基地”不是基地吗？关于水电离的常见误解可能阻碍药物的发现和开发。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c01783

Robert Fraczkiewicz

引用次数: 0

Targeting the Mitochondrial Protease ClpP for Anticancer Therapy. 靶向线粒体蛋白酶ClpP的抗癌治疗。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c01315

Zhongli Xu,Dmitry Pokushalov,Md Kabir,Youngeun Lee,Mrittika Chattopadhyay,Edmund C Jenkins,Cessarina Choo,H Ümit Kaniskan,Doris Germain,Jian Jin

引用次数: 0

Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis. Lenacapavir的发现：每年两次用于HIV-1治疗和暴露前预防的一流衣壳抑制剂。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-10-01 DOI: 10.1021/acs.jmedchem.5c01625

Eda Canales,Winston Tse,Scott D Schroeder,Chien-Hung Chou,Qi Liu,Jennifer Zhang,Scott E Lazerwith,Philip Morganelli,Roland D Saito,Gediminas Brizgys,Jiayao Li,Qiaoyin Wu,Michael Graupe,Randall L Halcomb,Manoj Desai,Carina Cannizzaro,Eric Hu,Jason K Perry,Armando G Villaseñor,John R Somoza,Ryan D Ferrao,S Swaminathan,Jim Zheng,Bing Lu,Judy Mwangi,Kelly Wang,Raju Subramanian,Bill J Smith,Gerry Rhodes,William Rowe,Dorothea Sauer,Latesh Lad,Giuseppe A Papalia,Sheila Clancy,George J Stepan,Helen Yu,Roman Sakowicz,Bing Shi,Gavin Carr,Rujuta A Bam,Luong K Tsai,Eric Singer,Derek Hansen,Andrew Mulato,Stephen R Yant,Tomas Cihlar,John O Link

{"title":"Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis.","authors":"Eda Canales,Winston Tse,Scott D Schroeder,Chien-Hung Chou,Qi Liu,Jennifer Zhang,Scott E Lazerwith,Philip Morganelli,Roland D Saito,Gediminas Brizgys,Jiayao Li,Qiaoyin Wu,Michael Graupe,Randall L Halcomb,Manoj Desai,Carina Cannizzaro,Eric Hu,Jason K Perry,Armando G Villaseñor,John R Somoza,Ryan D Ferrao,S Swaminathan,Jim Zheng,Bing Lu,Judy Mwangi,Kelly Wang,Raju Subramanian,Bill J Smith,Gerry Rhodes,William Rowe,Dorothea Sauer,Latesh Lad,Giuseppe A Papalia,Sheila Clancy,George J Stepan,Helen Yu,Roman Sakowicz,Bing Shi,Gavin Carr,Rujuta A Bam,Luong K Tsai,Eric Singer,Derek Hansen,Andrew Mulato,Stephen R Yant,Tomas Cihlar,John O Link","doi":"10.1021/acs.jmedchem.5c01625","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01625","url":null,"abstract":"The HIV capsid is essential to the virus lifecycle, making it a promising target for therapeutic intervention. In 2006, a screening campaign was initiated to identify small molecules capable of disrupting the protein-protein interactions required for self-assembly of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped capsid. Numerous compound design cycles over many years were undertaken to discover the complex structural elements that together afford the multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir has demonstrated robust efficacy for both HIV-1 treatment and prevention, and, remarkably, achieved 100% protection in women for the first time. These findings represent a significant advancement in treatment and prevention of HIV-1 infection, offering the potential to profoundly impact the global course of the HIV epidemic.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum: SAR Analysis, Mode of Action and In Vivo Studies. 荧光马里诺喹啉衍生物作为恶性疟原虫抑制剂：SAR分析、作用方式和体内研究。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c00138

Patricia Santos Barbosa,Guilherme Eduardo Souza,Sarah El Chamy Maluf,Vinícius Bonatto,Caio Silva Moura,Giovana Rossi Mendes,Talita Alvarenga Valdes,Yasmin Annunciato,Barbara Dos Santos Rossetto,Priscilla Dantas de Souza Ventura,Gilberto Gaspar Duarte Ortin,Wellington da Silva,Marcelo Yudi Icimoto,Amália Dos Santos Ferreira,Fabio C Cruz,Carolina B G Teles,Dhelio B Pereira,Gustavo Capatti Cassiano,Sofia Santana,Miguel Prudêncio,Camila S Barbosa,Igor M R Moura,Renan Marcel Giampauli,Irene Layane De Sousa,Silvana Aparecida Rocco,Marcos L Gazarini,Carlos Roque Duarte Correia,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido

{"title":"Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum: SAR Analysis, Mode of Action and In Vivo Studies.","authors":"Patricia Santos Barbosa,Guilherme Eduardo Souza,Sarah El Chamy Maluf,Vinícius Bonatto,Caio Silva Moura,Giovana Rossi Mendes,Talita Alvarenga Valdes,Yasmin Annunciato,Barbara Dos Santos Rossetto,Priscilla Dantas de Souza Ventura,Gilberto Gaspar Duarte Ortin,Wellington da Silva,Marcelo Yudi Icimoto,Amália Dos Santos Ferreira,Fabio C Cruz,Carolina B G Teles,Dhelio B Pereira,Gustavo Capatti Cassiano,Sofia Santana,Miguel Prudêncio,Camila S Barbosa,Igor M R Moura,Renan Marcel Giampauli,Irene Layane De Sousa,Silvana Aparecida Rocco,Marcos L Gazarini,Carlos Roque Duarte Correia,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido","doi":"10.1021/acs.jmedchem.5c00138","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00138","url":null,"abstract":"We present insights into the mechanism of action of marinoquinolines (MQ), a novel class of lead candidates. Using a divergent synthetic approach, we developed a series of 20 new analogues with fluorescence properties. Structure-activity relationships analysis identified 19 as an attractive compound showing a combination of favorable in vitro (IC503D7 = 0.28 μM; CC50HepG2 = 53 μM), ex vivo (EC50Pf = 1.2 μM; EC50Pv = 0.53 μM), in vivo (3 × 50 mg/kg oral dose resulted in a 96% reduction in parasitemia in Plasmodium berghei-infected mice), physicochemical (Sol7.4 = 171 μM; LogD7.4 = 3.9), and pharmacokinetic (P_app = 9.4 × 10-6 cm/s, human Clinthep,mic = 0.61-0.68 μL min-1 mg-1) properties. Compound 19 selectively accumulates in infected erythrocytes, enters the digest vacuole and inhibits Plasmodium falciparum proteolytic activity, suggesting that MQs act as protease inhibitors. These findings strengthen the evidence that MQs are promising lead candidates for antimalarial drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Synthesis of Phosphonate Derivatives of Benzisoselenazolones and Their Remarkable Antiureolytic Activity in Helicobacter pylori Cells. 苯并异硒唑酮膦酸盐衍生物的合成及其对幽门螺杆菌细胞的抗溶尿作用。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01385

Marta Grabarek,Wojciech Tabor,Paweł Krzyżek,Julia Bąkowicz,Agnieszka Grabowiecka,Łukasz Berlicki,Artur Mucha

{"title":"Synthesis of Phosphonate Derivatives of Benzisoselenazolones and Their Remarkable Antiureolytic Activity in Helicobacter pylori Cells.","authors":"Marta Grabarek,Wojciech Tabor,Paweł Krzyżek,Julia Bąkowicz,Agnieszka Grabowiecka,Łukasz Berlicki,Artur Mucha","doi":"10.1021/acs.jmedchem.5c01385","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01385","url":null,"abstract":"The attachment of a nickel-ion-complexing functionality to the structures of covalent inhibitors of ureases has been considered an effective method for enhancing binding to these pivotal virulence factors of various microbial pathogens. Following this approach, we envisioned a structural combination of 1,2-benzisoselenazol-3(2H)-one, a scaffold that produced the most significant antiureolytic effect achieved, with a phosphonic acid group intended to block the function of nickel ions in the catalytic mechanism. The multistep preparation of hybrid compounds involved aminolysis of 2-(chloroseleno)benzoyl chloride with the key diethyl aminophosphonate intermediates, followed by hydrolysis of the final phosphonate esters. Although not entirely consistent with the rationale of the design idea, the esters themselves, rather than the corresponding acids, demonstrated more substantial inactivation of the model Sporosarcina pasteurii urease and inhibition of ureolysis in Helicobacter pylori. In particular, IC50 values in pathogen cells reached an unprecedented range of 30-40 nM for some compounds.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma. 发现一种具有有效抗增殖活性的选择性强效BCL6 PROTAC治疗弥漫性大b细胞淋巴瘤。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01237

Xiaoli Yu,Xueyan Liao,Jingyu Zhang,Hanlin Wang,Xian Li,Jialiang Lu,Huan Zhou,Mingfei Wu,Yuheng Jin,Xin Zhu,Lei Xu,Shenxin Zeng,Youlu Pan,Jia Li,Jinxin Che,Yubo Zhou,Xiaowu Dong

{"title":"Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma.","authors":"Xiaoli Yu,Xueyan Liao,Jingyu Zhang,Hanlin Wang,Xian Li,Jialiang Lu,Huan Zhou,Mingfei Wu,Yuheng Jin,Xin Zhu,Lei Xu,Shenxin Zeng,Youlu Pan,Jia Li,Jinxin Che,Yubo Zhou,Xiaowu Dong","doi":"10.1021/acs.jmedchem.5c01237","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01237","url":null,"abstract":"B-cell lymphoma 6 (BCL6) is a key transcriptional repressor implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). However, current BCL6-targeting agents demonstrate restricted efficacy in vitro and in vivo, and the underlying mechanism remains unclear. In this study, we identified A19 as a potent BCL6 PROTAC through comprehensive structure-activity relationship (SAR) analysis. A19 induces rapid and efficient BCL6 degradation (DC50 = 34 pM in OCI-LY1 cells) and displays superior antiproliferative activity compared to the molecular glue BI3802 across multiple DLBCL cell lines. In addition, RNA-seq profiling showed that A19 and BI3802 trigger comparable changes in signaling pathways, reflecting similar transcriptomic responses. Further, oral dosing of A19 led to BCL6 degradation and inhibition of tumor growth in vivo. Overall, A19 is a valuable chemical tool and a promising lead compound toward the development of BCL6-dependent DLBCL.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Bitopic A3 Adenosine Receptor Molecular Probes: Positive Allosteric Modulation and Noncanonical Activation. 双位A3腺苷受体分子探针：正变构调节和非规范激活。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01985

Siva Hariprasad Kurma,Matteo Pavan,Tina C Wan,Balaram Pradhan,Marc López-Cano,Francisco Ciruela,Zhan-Guo Gao,John A Auchampach,Kenneth A Jacobson

{"title":"Bitopic A3 Adenosine Receptor Molecular Probes: Positive Allosteric Modulation and Noncanonical Activation.","authors":"Siva Hariprasad Kurma,Matteo Pavan,Tina C Wan,Balaram Pradhan,Marc López-Cano,Francisco Ciruela,Zhan-Guo Gao,John A Auchampach,Kenneth A Jacobson","doi":"10.1021/acs.jmedchem.5c01985","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01985","url":null,"abstract":"1H-Imidazo[4,5-c]quinolin-4-amines are lipid-facing, positive allosteric modulators (PAMs) of the Gi-coupled A3 adenosine receptor (A3AR). Elongated amino-alkyl chains anchor these bitopic PAMs secondarily to anionic phospholipids in the membrane's inner leaflet. Varied terminal functionalities and introduced reporter groups, as well as N1-alkylation on the core heterocycle, substantially enhanced human A3AR agonist (Cl-IB-MECA) potency and efficacy in [35S]GTPγS binding and revealed ago-PAM activity. Docking calculations predicted N1-benzylation to reduce undesired orthosteric site binding. Fluorophores, biotin, click moieties, chemically reactive, and photouncaging groups were included. Compound 38 (MRS8435, 9-methylenes, 0.1-10 μM) achieved ∼300% agonist Emax without ago-PAM activity. 4-Methyl 36 and 4-iodo 46 substitution of N1-benzyl increased Cl-IB-MECA potency by 14.7- and 30.5-fold, respectively. 9-Methylene N1-benzyl derivatives 35 and 42 achieved high ago-PAM efficacy (∼77% Cl-IB-MECA Emax). Molecular dynamics simulations detected stable electrostatic phospholipid interactions while maintaining A3AR allosteric binding. Thus, we rationally expanded SAR of bitopic A3AR PAMs, including molecular probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"75 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach. 多学科片段杂交方法设计靶向锥虫PTR1的2-氨基苯并噻唑衍生物。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01799

Joanna Panecka-Hofman, Pasquale Linciano, Ina Pöhner, Edyta Dyguda-Kazimierowicz, Wiktoria Jedwabny, Giacomo Landi, Nuno Santarem, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Rosaria Luciani, Stefania Ferrari, Daniele Aiello, Stefano Mangani, Cecilia Pozzi, Anabela Cordeiro-da-Silva, Sheraz Gul, Maria Paola Costi, Rebecca C Wade

{"title":"Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach.","authors":"Joanna Panecka-Hofman, Pasquale Linciano, Ina Pöhner, Edyta Dyguda-Kazimierowicz, Wiktoria Jedwabny, Giacomo Landi, Nuno Santarem, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Rosaria Luciani, Stefania Ferrari, Daniele Aiello, Stefano Mangani, Cecilia Pozzi, Anabela Cordeiro-da-Silva, Sheraz Gul, Maria Paola Costi, Rebecca C Wade","doi":"10.1021/acs.jmedchem.5c01799","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01799","url":null,"abstract":"Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as I bind a different region of the Trypanosoma brucei PTR1 (TbPTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against TbPTR1 and Leishmania major PTR1 (LmPTR1). In the first series, five compounds were synthesized, and 1a and 1b emerged as potent TbPTR1 inhibitors, with 1b also being active against LmPTR1 and moderately effective against Leishmania infantum. Furthermore, structure-activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than I.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Rigidity vs Activity: Design of Gramicidin S Analogs against Multidrug-Resistant Bacteria Based on Molecular Engineering. 刚性与活性：基于分子工程设计抗多重耐药细菌的革兰西菌素S类似物。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01234

Mikołaj Śleziak,Jarosław J Panek,Tomasz Janek,Aneta Jezierska,Monika Kijewska

{"title":"Rigidity vs Activity: Design of Gramicidin S Analogs against Multidrug-Resistant Bacteria Based on Molecular Engineering.","authors":"Mikołaj Śleziak,Jarosław J Panek,Tomasz Janek,Aneta Jezierska,Monika Kijewska","doi":"10.1021/acs.jmedchem.5c01234","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01234","url":null,"abstract":"Antimicrobial peptides are a promising class of therapeutics to address antibiotic resistance; yet, their clinical use is limited by toxicity and narrow-spectrum activity. To better understand how conformational rigidity influences efficacy and safety, a series of β-sheet antimicrobial peptide analogs based on gramicidin S were designed and synthesized. Two stapled derivatives (GSC-FB and GSC-SS) and a flexible linear analog (GS-L) were prepared and evaluated. GSC-FB retained potent activity against Gram-positive bacteria with a significantly reduced cytotoxicity. GS-L, characterized by increased conformational flexibility, showed broader-spectrum activity, including activity against Gram-negative strains, and similarly improved safety. Circular dichroism spectroscopy revealed that all analogs displayed structural perturbations relative to native gramicidin S. Molecular dynamics simulations indicated that only flexible or moderately rigid analogs effectively interact with membrane models. These findings demonstrate that conformational rigidity is a key parameter in the design of antimicrobial peptides, enabling the optimization of antimicrobial potency while mitigating toxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"54 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Virtual Screening and Multistage Computational Profiling of Small-Molecule Inhibitors Targeting Clostridioides difficile Toxin B. 艰难梭菌毒素B小分子抑制剂的虚拟筛选和多阶段计算分析。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI: 10.1021/acs.jmedchem.5c01483

Runze Wang,Qiuyu Zhang,Yi Lin,Yangpei Huang,Yuanfei Yang,Chaoqiang Ni,Chaoqiao Wang,Shuangshuang Wan

{"title":"Virtual Screening and Multistage Computational Profiling of Small-Molecule Inhibitors Targeting Clostridioides difficile Toxin B.","authors":"Runze Wang,Qiuyu Zhang,Yi Lin,Yangpei Huang,Yuanfei Yang,Chaoqiang Ni,Chaoqiao Wang,Shuangshuang Wan","doi":"10.1021/acs.jmedchem.5c01483","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01483","url":null,"abstract":"Clostridioides difficile infection (CDI), a leading cause of antibiotic-associated diarrhea, is driven by the virulence factor toxin B (TcdB), whose receptor-binding interfaces (RBIs) exhibit evolutionary divergence into α and β subtypes with distinct host-receptor specificities. Leveraging this insight, we developed a multistage computational pipeline to repurpose FDA-approved drugs as pan-RBI, pan-subtype TcdB inhibitors. Virtual screening of 10,027 compounds against AlphaFold3-predicted TcdB1-8 structures, integrated with molecular docking (AutoDock Vina/LeDock), MM/GBSA binding free energy calculations, and molecular dynamics simulations, prioritized three candidates. Dirlotapide (DB11399) emerged as the lead compound, demonstrating high-affinity binding to TcdB2 via surface plasmon resonance (SPR) and triggering partial unfolding of its α-helical structure as measured by circular dichroism (CD). In vitro, Dirlotapide rescued Caco-2 cells from cytotoxicity induced by all four major TcdB subtypes. Following rectal administration in mice, it protected against TcdB2-induced colonic damage, restored epithelial integrity, and significantly reduced proinflammatory cytokines (IL-6, TNF-α). Validation of gut-restricted pharmacokinetics, intestinal permeability, CYP450 interactions, and low nephrotoxicity supports its translational potential. Dirlotapide represents a rapidly repositionable anti-TcdB agent that neutralizes clinically relevant subtypes through dual RBI blockade.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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