Bioorganic Chemistry最新文献_第5页

MAP4K3/GLK: Structure, molecular pharmacology and drug development. MAP4K3/GLK：结构、分子药理学和药物开发。

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-27 DOI: 10.1016/j.bioorg.2025.109043

Jingwen Wang, Xiaoe Yan, Haibo Li, Yudao Shen, Caihong Yun, Jianming Zhang

引用次数: 0

Fluorescent Triazolyl unnatural amino acids in protein engineering: Encoding super folder green fluorescent protein and spectroscopic study. 荧光三唑基非天然氨基酸在蛋白质工程中的应用：超级文件夹绿色荧光蛋白的编码和光谱研究。

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-27 DOI: 10.1016/j.bioorg.2025.109045

Subhendu Sekhar Bag, Aniket Banerjee, Sinchini Barman, Sankalp Tiwari

{"title":"Fluorescent Triazolyl unnatural amino acids in protein engineering: Encoding super folder green fluorescent protein and spectroscopic study.","authors":"Subhendu Sekhar Bag, Aniket Banerjee, Sinchini Barman, Sankalp Tiwari","doi":"10.1016/j.bioorg.2025.109045","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109045","url":null,"abstract":"<p><p>CuAAC-derived fluorescent unnatural amino acids (FTUAAs) have been highly advantageous owing to their enhanced stability, increased resistance to proteolysis, better biocompatibility, and modulated photophysics. However, such a unique class of amino acids has never been previously incorporated into desired protein sequences using the genetic code expansion (GCE) approach. Herein, we have reported our pioneering efforts towards the site-specific incorporation of several novel FTUAAs into the 150th codon position of Super Folder Green Fluorescent Protein (sfGFP), followed by their expression in E. coli cells and the study of their photophysics. A Methanosarcina mazei-derived pyrrolysyl-tRNA synthetase, namely Tet 3.0 aaRS, and its corresponding tRNA pair have been utilised in these studies. The results have indicated the efficient incorporation of all the unnatural amino acids in different experimental settings. Studies of photophysical properties, MALDI TOF mass analysis, fluorescence microscopy, and molecular docking have validated our claims. In fact, the incorporation of FTUAAs into reporter sfGFP using the GCE technique has potentially opened up a gateway for incorporating amino acids containing an integral triazole moiety into any protein sequence to expand their functionalities. Incorporating FTUAAs can also help intrinsically label proteins to understand their roles in various molecular pathways, among other applications.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109045"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224643","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}

引用次数: 0

The role and potential therapeutic application of HDAC6 inhibitors in inflammation-related diseases: A medicinal chemistry perspective. HDAC6抑制剂在炎症相关疾病中的作用及潜在治疗应用：药物化学视角

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-27 DOI: 10.1016/j.bioorg.2025.109052

Bo Han, Niubing Sun, Mengfei Wang, Anqi Shen, Xuezhi Yang, Qingwei Zhang

{"title":"The role and potential therapeutic application of HDAC6 inhibitors in inflammation-related diseases: A medicinal chemistry perspective.","authors":"Bo Han, Niubing Sun, Mengfei Wang, Anqi Shen, Xuezhi Yang, Qingwei Zhang","doi":"10.1016/j.bioorg.2025.109052","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109052","url":null,"abstract":"<p><p>Histone deacetylase 6 (HDAC6), as the most structurally and functionally unique member of the HDAC family, mediates the deacetylation process of various histone or non-histone substrates. Broad biological functions promote HDAC6 to involve a variety of physiological processes, particularly plays an important role in the pathological process of inflammation. HDAC6 activates the NF-κB signaling pathway through deacetylation, upregulating the expression of inflammation-related genes (e.g. TNF, NLRP3 and IL1B). Additionally, HDAC6 also participates in NLRP3 inflammasome activation through its ZnF-UBP domain, thereby resulting in the release of various inflammatory cytokines. Notably, several conventional HDAC6 inhibitors have exhibited promising therapeutic effects in various inflammation-related disease models. These findings underscore the potential of HDAC6 as a therapeutic target, and some explorations of novel HDAC6 inhibitors for treating inflammation have been reported recently. Herein, we summarized the critical role of HDAC6 in inflammation, highlight recent advances of HDAC6 inhibitors in inflammation treatment and propose some insights about future development from the perspective of medicinal chemistry, aiming to provide some guidance for the application of HDAC6 inhibitors in inflammation-related diseases.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109052"},"PeriodicalIF":4.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197526","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}

引用次数: 0

Antiplatelet therapy through inhibition of P2Y12 and phosphodiesterase receptors by novel synthesis 1,3-dicyclohexylpyrimidine-2,4(1H,3H)-dione derivatives with computational evaluation. 新型合成1,3-双环己基嘧啶-2,4(1H,3H)-二酮衍生物通过抑制P2Y12和磷酸二酯酶受体的抗血小板治疗

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-26 DOI: 10.1016/j.bioorg.2025.109009

Doaa A Elsayed, Moustafa K Soltan, Mansoura Ali Abd-El-Maksoud, Eman S Tantawy, Ahmed F El-Sayed, Wesam S Shehab, Aamer Saeed, Basant Farag

{"title":"Antiplatelet therapy through inhibition of P2Y12 and phosphodiesterase receptors by novel synthesis 1,3-dicyclohexylpyrimidine-2,4(1H,3H)-dione derivatives with computational evaluation.","authors":"Doaa A Elsayed, Moustafa K Soltan, Mansoura Ali Abd-El-Maksoud, Eman S Tantawy, Ahmed F El-Sayed, Wesam S Shehab, Aamer Saeed, Basant Farag","doi":"10.1016/j.bioorg.2025.109009","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109009","url":null,"abstract":"<p><p>In this study, we report the synthesis of a new class of 1,3-dicyclohexylpyrimidine-2,4-dione derivatives with potential antiplatelet activity. The novelty of this work lies in the development of unprecedented pyrimidine-based scaffolds, prepared through simple synthetic routes, and their evaluation as dual inhibitors of P2Y12 and phosphodiesterase 5 receptors. Biological assays demonstrated that compound 10 was the most active P2Y12 inhibitor (IC50 = 0.271 ± 0.009 μg/ml), surpassing reference drug clopidogrel (IC50 = 0.327 ± 0.011 μg/ml). Compound 10 also exhibited potent PDE5 inhibition, using sildenafil as a reference drug. Whereas compound 5 showed the least activity in both of these biological assays. Frontier molecular orbital analyses demonstrated compound 15 showed the smallest energy gap, suggesting easier electron transfer, and had the highest EA, strengthening adherence to nucleophilic residues among the tested compounds. Molecular docking studies revealed strong binding affinities of synthesized compounds toward both P2Y12 and PDE5, supporting the biological findings. ADMET profiling confirmed that compound 10 complies with Lipinski's rule of five and possesses favorable bioavailability, drug-likeness, and low predicted toxicity. Molecular dynamics simulations further validated its stability, showing consistent RMSD, RMSF, Rg, and SASA values, indicative of robust receptor-ligand interactions toward both P2Y12 and PDE5. Overall, this work introduces a novel pyrimidine-based scaffold with dual inhibitory activity, combining experimental and computational validation. These findings not only highlight the role of pyrimidine derivatives in advancing antiplatelet therapy but also provide a strong basis for further development of compound 10 as a potential lead for cardiovascular disease management.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109009"},"PeriodicalIF":4.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243436","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}

引用次数: 0

Aggregation inhibitors of tau protein with anti-inflammatory potential against neurodegeneration 具有抗神经退行性变抗炎潜能的tau蛋白聚集抑制剂

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-24 DOI: 10.1016/j.bioorg.2025.109030

Bilal Nehmeh , Alia Khalil , Jana Tfaili , Wissam H. Faour , Elias Akoury

{"title":"Aggregation inhibitors of tau protein with anti-inflammatory potential against neurodegeneration","authors":"Bilal Nehmeh , Alia Khalil , Jana Tfaili , Wissam H. Faour , Elias Akoury","doi":"10.1016/j.bioorg.2025.109030","DOIUrl":"10.1016/j.bioorg.2025.109030","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by two pathological hallmarks: extracellular β-amyloid plaques and intracellular neurofibrillary tangles (NFTs) formed by aggregated Tau protein. Ongoing research focuses on identifying inhibitors that either block Tau aggregation or destabilize pre-formed fibrils. In this study, we evaluated derivatives of Rhodanine (RDN), Anthraquinone (AQ), Phenylaminopyrimidine (PhNH<sub>2</sub>), Phenylthiazol hydrazide (PTH) and Benzothiazole (BZT) as potential modulators of Tau aggregation. We synthesized target compounds using Pd- and Cu-catalyzed coupling reactions and confirmed their structures via NMR spectroscopy. Thioflavin T fluorescence assays and <sup>1</sup>H<img><sup>15</sup>N Heteronuclear Single Quantum Coherence (HSQC) NMR experiments demonstrated that PhNH<sub>2</sub> and PTH effectively inhibited Tau polymerization by interacting with key hexapeptide motifs. Additionally, AQ, RDN, and PhNH<sub>2</sub> reduced iNOS and COX-2 expression in LPS-stimulated monocytes, underscoring their anti-inflammatory activity. These findings suggest PhNH<sub>2</sub> and PTH as promising candidates for modulating Tau aggregation, with PhNH<sub>2</sub> exhibiting dual anti-aggregation and anti-inflammatory properties.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109030"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154883","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}

引用次数: 0

Smart drug in cancer treatment: Design, synthesis and biophysical characterization of uracil-containing cyclic hypervalent iodine (Uracil-BX) reagent with G-quadruplex DNA structures 癌症治疗中的智能药物：具有g -四重DNA结构的含尿嘧啶环高价碘（尿嘧啶- bx）试剂的设计、合成和生物物理表征

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-23 DOI: 10.1016/j.bioorg.2025.109021

Sukanya Das , Sagar Bag , Md. Abbasuddin Sk , Raj K. Nandi , Sudipta Bhowmik

{"title":"Smart drug in cancer treatment: Design, synthesis and biophysical characterization of uracil-containing cyclic hypervalent iodine (Uracil-BX) reagent with G-quadruplex DNA structures","authors":"Sukanya Das , Sagar Bag , Md. Abbasuddin Sk , Raj K. Nandi , Sudipta Bhowmik","doi":"10.1016/j.bioorg.2025.109021","DOIUrl":"10.1016/j.bioorg.2025.109021","url":null,"abstract":"<div><div>G-Quadruplex DNA (GQ-DNA) is a significant non-canonical nucleic acid structure found in crucial genomic regions, particularly in the promoter as well as telomere areas of various oncogenes. GQ-DNA is recognized as a key target for anticancer therapies, highlighting the importance of studying its interactions with newly synthesized uracil-containing cyclic hypervalent iodine reagents, Uracil-BX. Given the polymorphic variability of GQ-DNA, it is vital to identify ligands that can selectively bind to specific quadruplex sequences. Various biophysical studies, were employed to explore these ligand's interaction with quadruplex and duplex DNAs. The synthesized compound 1,3-dimethyl-5-(3-oxo-1λ<sup>3</sup>-benzo[<em>d</em>][1,2]iodaoxol-1(3<em>H</em>)-yl)pyrimidine-2,4(1<em>H</em>,3<em>H</em>)-dione (Uracil-BX <strong>3a</strong>), preferentially interacts with VEGF (vascular endothelial growth factor) GQ-DNA, prevalently found in the oncogenic promoter regions. This finding also opens the door for more GQ biology research by highlighting the possibility of creating medications to comprehend the molecular elements of GQ-DNA recognition for hypervalent iodine reagents. This suggests that Uracil-BX <strong>3a</strong> may be a promising ligand for targeting VEGF GQ-DNA, potentially offering a strategy to regulate gene expression in cancer cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109021"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154884","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}

引用次数: 0

Discovery of W478, a novel SHMT2 inhibitor for the treatment of esophageal carcinoma 新型SHMT2抑制剂W478的发现治疗食管癌

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-23 DOI: 10.1016/j.bioorg.2025.109028

Hafiz Muhammad Bilal Akram , Yulin Liu , Jianshu Dong , Xueke Zhao , Lidong Wang , Wen Zhao , Hongmin Liu , Liying Ma , Cong Han

{"title":"Discovery of W478, a novel SHMT2 inhibitor for the treatment of esophageal carcinoma","authors":"Hafiz Muhammad Bilal Akram , Yulin Liu , Jianshu Dong , Xueke Zhao , Lidong Wang , Wen Zhao , Hongmin Liu , Liying Ma , Cong Han","doi":"10.1016/j.bioorg.2025.109028","DOIUrl":"10.1016/j.bioorg.2025.109028","url":null,"abstract":"<div><div>Esophageal cancer has been regarded as a serious malignancy due to its poor prognosis and high mortality rate. Serine hydroxymethyltransferase 2 (SHMT2) is emerging as an attractive target for esophageal cancer therapy. Compound W478 was identified as a potent SHMT2 inhibitor with an IC<sub>50</sub> value of 1.21 μM, especially whose chemical structure is distinct from the reported SHMT2 inhibitors. Both cellular thermal shift assay and isothermal titration calorimetry experiments showed that compound W478 tightly bound to SHMT2 (K<sub>D</sub> = 10.6 ± 1.2 μM). The molecular docking analysis revealed its binding at the folate binding site of SHMT2. Moreover, compound W478 exhibited a significant antiproliferative effect on human esophageal cancer cell lines, KYSE-450 and KYSE-70 cells (IC<sub>50</sub> = 1.62 μM, 1.18 μM, respectively). The wound healing and transwell assays showed that compound W478 could inhibit the migratory and invasive potential of KYSE-450 and KYSE-70 cells in a dose-dependent manner. Further studies demonstrated that compound W478 could induce cell arrest at the G2/M phase and promote cell apoptosis and ROS production in KYSE-450 and KYSE-70 cells. These findings indicated that compound W478 could serve as a promising lead compound for the development of SHMT2 inhibitor to address esophageal carcinoma.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109028"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155426","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}

引用次数: 0

Crystallographic fragment screening reveals new starting points for PYCR1 inhibitor design 晶体碎片筛选揭示了PYCR1抑制剂设计的新起点

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-23 DOI: 10.1016/j.bioorg.2025.109024

Wiktoria Ragin-Oh , Dominika Czerwonka , Linh H. Tran , Giuseppe Forlani , Milosz Ruszkowski

{"title":"Crystallographic fragment screening reveals new starting points for PYCR1 inhibitor design","authors":"Wiktoria Ragin-Oh , Dominika Czerwonka , Linh H. Tran , Giuseppe Forlani , Milosz Ruszkowski","doi":"10.1016/j.bioorg.2025.109024","DOIUrl":"10.1016/j.bioorg.2025.109024","url":null,"abstract":"<div><div>Pyrroline-5-carboxylate (P5C) reductase catalyzes the final step in proline biosynthesis. Human P5C reductase isoform 1 (PYCR1) has emerged as a key metabolic enzyme supporting cancer progression through its roles in redox homeostasis, collagen production, and the proline-P5C cycle. Despite its relevance as a therapeutic target, structural and chemical efforts to inhibit PYCR1 remain limited and have largely focused on proline analogs. Here, we report the first crystallographic fragment screening (XFS) campaign against PYCR1, employing a chemically diverse library of 96 compounds. We solved twelve co-crystal structures, featuring ligands occupying the P5C and NADH binding pockets, including dual-site ligands that span both regions. Among the newly identified moieties, sulfonamide and sulfamate groups emerged as notable isosteric replacements for the carboxylate group in the PYCR1 active site. Aromatic substituents in several compounds revealed a cryptic subpocket near the nicotinamide-binding site. Interestingly, halogen-substituted aromatic rings, often present in known PYCR1 inhibitors, exhibited distinct binding orientations, reflecting the flexibility and diversity of interactions in the binding subpockets. High-resolution structures revealed ligand-induced conformational changes in PYCR1, some involving significant rearrangements. Molecular dynamics simulations indicated that these conformations are accessible in the ligand-free enzyme, underscoring the intrinsic plasticity of PYCR1's active site.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109024"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155428","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}

引用次数: 0

Multimodal profiling of Pepcan-CB1 receptor structure-activity relationships: integrating molecular dynamics simulations, biological profiling, and the deep learning model MuMoPepcan Pepcan-CB1受体结构-活性关系的多模态分析：整合分子动力学模拟、生物学分析和深度学习模型MuMoPepcan

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-23 DOI: 10.1016/j.bioorg.2025.109027

Hongyang Man , Huiming Bao , Zhanyu Niu , Zhonghua Zhang , Jerine Peter Simon , Tong Yang , Pengtao Li , Shouliang Dong

{"title":"Multimodal profiling of Pepcan-CB1 receptor structure-activity relationships: integrating molecular dynamics simulations, biological profiling, and the deep learning model MuMoPepcan","authors":"Hongyang Man , Huiming Bao , Zhanyu Niu , Zhonghua Zhang , Jerine Peter Simon , Tong Yang , Pengtao Li , Shouliang Dong","doi":"10.1016/j.bioorg.2025.109027","DOIUrl":"10.1016/j.bioorg.2025.109027","url":null,"abstract":"<div><div>In machine learning of drug discovery, the scale of accessible data is often strictly limited, while few-shot learning in wet-lab experimental data limits the accuracy of machine learning algorithms. Cannabinoid receptors are involved in various important physiological activities, and pepcans are key components of the endocannabinoid system. Herein, we proposed a combined dry-wet lab experimental framework that incorporated molecular dynamics simulation (MDS) data into peptide biological activity prediction. We validated our hypothesis on cannabinoid receptors type 1 (CB1) and pepcans: (1) In the study, we synthesized 45 pepcan peptides to establish a bioactivity dataset and identified RD-pepcan-11 as an lead analgesic compound by Bioscreening, with systematic characterization of its CB1 selectivity and pharmacodynamics.; (2) Millions of conformational data were generated by MDS and a CB1-pepcans conformation dataset was constructed; (3) Combining wet-lab data and MDS data, a deep learning model - MuMoPepcan was developed, reducing prediction errors to within the error range of wet-lab experiments. This study not only identified novel high-potential pepcans - RD-pepcan-11, but also demonstrated that MDS can serve as an effective data augmentation method to scale up drug-receptor datasets, thereby improving model generalizability and performance.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109027"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154881","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}

引用次数: 0

Identification of novel selective estrogen receptor degraders (SERD) via physics-based and deep-learning-based virtual screening and Bioassys 通过基于物理和深度学习的虚拟筛选和Bioassys鉴定新型选择性雌激素受体降解物（SERD）

IF 4.7 2区医学

Bioorganic Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.bioorg.2025.109011

Mengyu Chen , Hao Zhang , Shiyun Chen , Pengying Liang , Zengye Wu , Xiaoya Gao , Jun Chen , Shaoyu Wu , Jiajie Zhang , Yuanxin Tian

{"title":"Identification of novel selective estrogen receptor degraders (SERD) via physics-based and deep-learning-based virtual screening and Bioassys","authors":"Mengyu Chen , Hao Zhang , Shiyun Chen , Pengying Liang , Zengye Wu , Xiaoya Gao , Jun Chen , Shaoyu Wu , Jiajie Zhang , Yuanxin Tian","doi":"10.1016/j.bioorg.2025.109011","DOIUrl":"10.1016/j.bioorg.2025.109011","url":null,"abstract":"<div><div>Breast cancer is the most common malignant tumor among women, most of which are ERα(Estrogen Receptor alpha) positive. SERDs(Selective Estrogen Receptor Degraders), such as Fulvestrant(the first SERD), can induce degradation of this receptor, leading to overcome the acquired endocrine resistance. However, only two SERDs (Fulvestrant and Elacestrant) are currently clinically approved, highlighting an urgent demand for novel, oral, and more potent alternatives. In this study we developed a multi-tiered virtual screening combing physics-based docking methods (Glide) with deep-learning-based docking methods (Karmadock and Carsidock) to identify SERDs with novel scaffold. After ADMET and MM-GBSA screening, four purchasable candidate compounds were selected for biological evaluation in three cell lines. Among them, two compounds exhibited significant anti-proliferation activity aganist ER-positive cells. The fingerprint analysis also revealed their structural novelty, which are distinct from the known SERDs. Further study indicated F0840–0093 could directly bound to ERα and induced its proteasomal degradation (mimicking Fulvestrant). In summary, our work not only provided a feasible virtual screening approach in drug discovery but also identified some compounds, particularly F0840–0093, which can be a promising lead with new chemical scaffold for further optimization and development as SERDs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109011"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154882","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}

引用次数: 0