Bioorganic Chemistry最新文献

{"title":"A tumor-targeting strategy based on covalent aptamer-carborane conjugates.","authors":"Xiaolu Zhou, Shaokang Jia, Shengjie Xie, Shanshan Qin, Xiang Zhou","doi":"10.1016/j.bioorg.2026.110553","DOIUrl":"10.1016/j.bioorg.2026.110553","url":null,"abstract":"<p><p>The development of tumor-targeting agents is of great significance for cancer therapy. Despite the promising potential of Boron Neutron Capture Therapy (BNCT), efficient and selective accumulation of boron-10 agents in cancer cells remains challenging. Conjugation of carborane with tumor-targeting ligands provides an alternative strategy for selective accumulation in the vicinity of cancer cells. In this study, we designed and synthesized aptamer-carborane derivatives, named AS1411-CB conjugates, via covalent linkage between a dodecahydro-arachno-bis(acetonitrile)decaborane and the DNA aptamer AS1411. AS1411 specifically binds to nucleolin, which is frequently overexpressed on the surface of cancer cells, thus enables selective targeting. Circular dichroism analysis indicated that AS1411-CB conjugates retained the characteristic G-quadruplex conformation of AS1411. Incorporation of a 5-Carboxyfluorescein (FAM) fluorescent label on AS1411 allowed flow cytometry analysis, which demonstrated significantly higher association of AS1411-CB conjugates with MCF-7 breast cancer cells compared with MCF-10 A normal mammary epithelial cells. Confocal microscopy further confirmed preferential localization of AS1411-CB conjugates on the surface of MCF-7 cells, consistent with nucleolin-mediated targeting. These results demonstrated that AS1411-CB conjugates preserved the targeting capability of AS1411 and highlighted its potential as a boron delivery platform for tumor-targeting applications.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"182 ","pages":"110553"},"PeriodicalIF":5.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014989","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}

{"title":"Targeting overexpressed tumor cell receptors with radiolabeled molecules: Biological targets, clinical applications, and translational challenges.","authors":"Seyed Jalal Hosseinimehr","doi":"10.1016/j.bioorg.2026.110519","DOIUrl":"10.1016/j.bioorg.2026.110519","url":null,"abstract":"<p><p>Cancer remains a leading cause of mortality worldwide, and early diagnosis and effective targeted therapy are often constrained by the lack of tumor-specific biomarkers. Overexpressed cell-surface receptors provide accessible targets for precision molecular imaging and radionuclide therapy, enabling selective visualization and treatment of malignancies while minimizing off-target effects in normal tissues. This review synthesizes the current landscape of biomarker-targeted radiopharmaceuticals, highlighting clinically approved agents, emerging molecular scaffolds, and key criteria for optimal targeting and imaging performance. Clinically approved PSMA- and SSTR2-targeted radiotracers exemplify the success of this approach, enabling highly sensitive and specific detection of prostate cancer and neuroendocrine tumors, respectively. In contrast, many other radiolabeled molecules face substantial challenges in regulatory approval and clinical translation. Overall, exploitation of overexpressed tumor biomarkers for targeted imaging and therapy holds considerable promise for transforming oncology diagnostics and improving patient outcomes through precision molecular medicine.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"182 ","pages":"110519"},"PeriodicalIF":5.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007660","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}

{"title":"2-Azabicyclo[3.2.1]octane-based ALK inhibitors inspired by aconitine scaffold remodeling: design, synthesis, and biological evaluation","authors":"Shuai Guo,&nbsp;Gong-hui Ge,&nbsp;Hao Hu,&nbsp;Ruo-jin wang,&nbsp;Wen-han Xue,&nbsp;Ting-ting Li,&nbsp;Yan-ping Wang,&nbsp;Xu Zhang,&nbsp;Yi-meng Zheng,&nbsp;Hong-ye Liu,&nbsp;Ying-hao Sun,&nbsp;Fan-hao Meng,&nbsp;Ting-jian Zhang","doi":"10.1016/j.bioorg.2026.110662","DOIUrl":"10.1016/j.bioorg.2026.110662","url":null,"abstract":"<div><div>Building on a previously reported aconitine-inspired 2-azabicyclo[3.2.1]octane scaffold, a series of derivatives was designed and synthesized as ALK-directed leads. Compound <strong>14n</strong> showed the lowest measured biochemical ALK IC₅₀ in the present series (0.73 nM) and a biochemical preference for ALK within the tested kinase panel. It retained inhibitory activity against ALK L1196M and G1202R, with IC₅₀ values of 10.5 and 88.7 nM, respectively. Compound <strong>14n</strong> exhibited antiproliferative activity in two ALK-positive cell lines, NCI-H2228 and Karpas-299, with IC₅₀ values of 0.06 and 0.69 μM, respectively. In NCI-H2228 cells, <strong>14n</strong> reduced ALK, AKT, and ERK phosphorylation, induced G0/G1-phase cell-cycle arrest and apoptosis, and reduced wound closure and Transwell migration. In an NCI-H2228 xenograft model, <strong>14n</strong> produced dose-dependent tumor growth inhibition. At 30 mg/kg, its antitumor effect was similar in magnitude to that of ceritinib at the same dose, with no overt toxicity observed under the tested conditions. Molecular docking and molecular dynamics simulations suggested a plausible binding mode within the ALK ATP-binding pocket. These findings identify <strong>14n</strong> as an ALK-directed lead for further optimization.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"183 ","pages":"Article 110662"},"PeriodicalIF":5.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149202806","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}

{"title":"In vitro enzymatic synthesis of long-acting therapeutic proteins and peptides.","authors":"Gaoshuai Li, Yanlu Zhang, Qicheng Zhu, Yongjun Mao, Yanchao Han, Chenshui Lin, Hongliang Duan, Xudong Wang","doi":"10.1016/j.bioorg.2026.110521","DOIUrl":"10.1016/j.bioorg.2026.110521","url":null,"abstract":"<p><p>The site-specific functionalization of therapeutic proteins and peptides represents a significant challenge in modern synthetic chemistry due to the presence of numerous competing nucleophilic residues. Conventional chemical conjugation strategies not only suffer from poor regioselectivity-leading to high product heterogeneity and compromised bioactivity-but also frequently rely on toxic organic solvents and excessive coupling reagents, directly contradicting the principles of green chemistry. In contrast, biocatalysis has become an effective approach for precision bioconjugation. Operating under mild aqueous conditions, enzymatic transformations offer high regio- and chemoselectivity, high atom economy, and minimal environmental footprint. This review focuses on recent advances in the biocatalytic synthesis of functionalized biomacromolecules, covering four highly efficient green modification strategies: enzymatic glycosylation, lipidation, PEGylation, and macrocyclization. The catalytic mechanisms, substrate specificities, and structural engineering of diverse enzyme classes (e.g., transglutaminases, transpeptidases, ligases, and glycosyltransferases) are discussed in the context of generating homogeneous bioconjugates. Furthermore, we analyze current biocatalytic bottlenecks, such as restricted substrate scopes for unnatural polymers, and provide perspectives on how artificial intelligence (AI)-driven generative enzyme design and synthetic biology will further broaden the scope of biocatalytic methods, promoting the sustainable biomanufacturing of long-acting therapeutic proteins and peptides.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"182 ","pages":"110521"},"PeriodicalIF":5.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011853","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}

{"title":"Integrating graph attention networks and deep learning with multi-stage computational screening: Bisdemethoxycurcumin as a potent A₂A receptor inhibitor for Parkinson's disease.","authors":"Khaled Otmanine, Mounir Hammoudi, Houari Bendriss, Brahim Feraoun, Selma Mekhane, Nesrine Gherioune, Cherrouk Benmehache, Ichraf Kerrouzi, Khadidja Ayadi, Khaled El Miloudi, Meryem Amal Benghalia, Mustapha Kamel Otmanine, Mohamed Hentabli","doi":"10.1016/j.bioorg.2026.110653","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.110653","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Parkinson's disease (PD) remains a progressive neurodegenerative disorder with limited disease modifying therapies, as current treatments such as L-DOPA offer only symptomatic relief and are associated with severe adverse effects. This study presents an integrated multi-stage computational pipeline that combines quantitative structure activity relationship (QSAR) modelling enhanced by graph attention networks (GATs), molecular docking, density functional theory (DFT), molecular dynamics (MD) simulations, and ADMET profiling to identify natural inhibitors targeting four key PD related proteins: adenosine A₂A receptor (A₂AR), gamma aminobutyric acid type A receptor (GABA-A), nuclear factor erythroid 2- related factor 2 (Nrf2), and (α-synuclein). A comprehensive dataset of 1393 structurally diverse compounds derived from 6- hydroxybenzothiazole 2-carboxamide and related scaffolds was assembled and used to train and validate seven regression algorithms. GATs achieved superior predictive performance (R&lt;sup&gt;2&lt;/sup&gt; = 0.991, Q&lt;sup&gt;2&lt;/sup&gt; = 0.987, RMSE = 0.487), outperforming Extra Trees (R&lt;sup&gt;2&lt;/sup&gt; = 0.742), Random Forest (R&lt;sup&gt;2&lt;/sup&gt; = 0.761), and SVR-RBF (R&lt;sup&gt;2&lt;/sup&gt; = 0.65). The large dataset size enhanced model generalizability, reduced overfitting risk, and enabled robust feature selection from an expanded descriptor pool of 312 molecular descriptors. Y-randomization with 100 permutations confirmed that all models with meaningful predictive performance were free from chance correlation (ΔQ&lt;sup&gt;2&lt;/sup&gt; &gt; 0.50), validating the robustness of the QSAR workflow. Molecular docking of six phytochemicals derived from Curcuma longa (ar-turmerone, α -turmerone, bisdemethoxycurcumin) and Salvia officinalis (camphor, 1,8-cineole, α, β-thujone) revealed that bisdemethoxycurcumin BDMC exhibited the strongest binding affinity to the A₂A receptor (-9.1 kcal/mol) among the evaluated phytochemicals. L-DOPA, the current clinical standard of care, displayed weak affinity to the A₂A receptor (-7.2 kcal/mol), consistent with its known mechanism as a dopamine precursor rather than an A₂A ligand. DFT calculations at the B3LYP/6311G(d,p) level showed that BDMC possessed the lowest HOMO- LUMO energy gap (0.1428 eV) and the highest electrophilicity index (ω = 0.1477), indicating superior chemical reactivity and electron accepting capacity. A 200 ns MD simulation confirmed stable BDMC A₂A receptor binding, with 3-8 (mean ≈ 5) persistent hydrogen bonds and no dissociation events throughout the trajectory, as evidenced by centre of mass distance analysis and principal component analysis. ADMET profiling using SwissADME and ProTox II classified BDMC as blood brain barrier (BBB) permeable, compliant with Lipinski's Rule of Five, and safe (LD₅₀ = 2560 mg/kg, toxicity Class 5), compared to L-DOPA (Class 4, LD₅₀ = 1460 mg/kg). Comparative analysis demonstrated that BDMC offers superior predicted binding affinity to the A₂A receptor and a more favourable predicted toxic","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"184 ","pages":"110653"},"PeriodicalIF":5.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219739","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}

{"title":"Corrigendum to \"Discovery of pyrimidine-2,4-diamine analogues as efficiency anticancer drug by targeting GTSE1\" [Bioorg. Chem. 151 (2024) 107700].","authors":"Sunhui Xing, Huamao Yang, Xiaojian Chen, Yan Wang, Shuyuan Zhang, Peipei Wang, Chaoyue Chen, Kun Wang, Zhiguo Liu, Xiaohui Zheng","doi":"10.1016/j.bioorg.2026.110283","DOIUrl":"10.1016/j.bioorg.2026.110283","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"110283"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597197","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}

{"title":"Chimeric pyrrolodiketo-pyrrolidine-phthalazine - triazole derivatives: synthesis, structure, stereochemistry, and anticancer activity.","authors":"Marius Savu, Vasilichia Antoci, Oana Elena Carp, Sergiu Shova, Cristina Mariana Uritu, Miruna Maria Furtuna, Maria-Cristina Al-Matarneh, Mitica Ciorpac, Dorina Amariucai-Mantu, Ionel I Mangalagiu","doi":"10.1016/j.bioorg.2026.110413","DOIUrl":"10.1016/j.bioorg.2026.110413","url":null,"abstract":"<p><p>We present herein a detailed study concerning the design, synthesis, structure, stereochemistry, and anticancer activity of a new class of chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole (PPPT) derivatives. The design of the chimeric PPPT molecules integrated the biological potential of phthalazine, pyrrolidine, and triazole scaffolds using the Multiple Targeting Ligands (MTL) / molecular hybridization (MH) strategy, along with bioisosteric modifications of existing drugs. The synthesis of our chimeric PPPT derivatives was efficient and straightforward in two steps: a Huisgen 3 + 2 dipolar cycloaddition reaction of ylides with a symmetrically substituted cyclic Z-alkene, followed by a click copper-catalysed reaction. The cycloaddition reactions proceed with high stereospecificity, and NMR and single-crystal X-ray diffraction studies unambiguously established the stereochemistry of the obtained compounds. The anticancer assay reveals that the newly obtained compounds 1, 4a,b, and 6a-j have low or no cytotoxicity toward normal cells and exhibit very good to moderate activity against breast adenocarcinoma and osteosarcoma cancer cell lines. The most active compounds were proved to be the chimeric derivatives 6c, 6d, and 6j, with IC₅₀ values close to those of the standard drug doxorubicin on the MCF7 and MG-63 cancer cell lines, and with selectivity index values also indicating a good cytotoxic profile. Notable SAR correlations have been observed. The in silico Swiss-ADME evaluation indicates that our chimeric PPPT derivatives exhibit good ADME, drug-likeness, and medicinal chemistry properties. The in silico computational Swiss-Target Prediction tool predicts that our chimeric PPPT compounds will most likely act as Multiple Targeting Ligands, primarily as tyrosine kinase and PARP-1 inhibitors. The in silico molecular docking studies confirm VEGFR-2 and PARP-1 as possible binding sites for our compounds. Both the experimental anticancer assay and the in silico computational studies suggest that our chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole derivatives 6c, 6d, and 6j are promising drug candidates.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110413"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786315","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}

{"title":"Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.","authors":"Nitin Kumar, Izhar Khan, Jyoti Singh, Krishan Kumar, Virendra Kumar Kushwaha, Smriti Ojha, Sunil Kumar Raman, Gauri Shankar","doi":"10.1016/j.bioorg.2026.110361","DOIUrl":"10.1016/j.bioorg.2026.110361","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110361"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756742","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}

{"title":"Design, synthesis and biological evaluation of novel 1,3,5-triazine derivatives containing benzo[d]imidazole scaffold as PI3K inhibitors.","authors":"Ju Liu, Nan Li, Runqi Zhang, Xiaozhe Jiang, Yunpeng Zhou, Congjun Xu, Jiaying Ao, Xiaomiao Wang, Chunyan Li, Jiwei Shen, Shi Ding, Ye Chen","doi":"10.1016/j.bioorg.2026.110333","DOIUrl":"10.1016/j.bioorg.2026.110333","url":null,"abstract":"<p><p>Twenty-seven novel 1,3,5-triazine derivatives containing benzo[d]imidazole scaffold were designed, synthesized, and evaluated for anti-tumor activity as PI3Kα inhibitors. Assessment of PI3Kα inhibitory effects revealed that some compounds were highly potent in vitro, with seventeen compounds (LNP1, LNP2, LNP4, LNP7-LNP10, LNP12-LNP18, LNP20, LNP23, and LNP24) showing IC₅₀ values less than 100 nM. Notably, LNP23 and LNP24 showed remarkable potency against PI3Kα with IC₅₀ values of 5.15 nM and 8.88 nM, respectively, and thus they were more potent than positive control drug ZSTK474 (PI3Kα, IC₅₀ = 9.89 nM). Compared with ZSTK474, LNP23 and LNP24 also exhibited increased selectivity for PI3Kα over other class I PI3K isoforms. Evaluation of some compounds on MDA-MB-231, MCF-7, and H1975 cell lines revealed that most of them possessed moderate to outstanding antiproliferative activities. LNP23 demonstrated marked inhibitory activity on cell proliferation, with IC₅₀ values of 6.85 μM (MDA-MB-231), 1.29 μM (MCF-7), and 2.13 μM (H1975). Antitumor mechanism of action of compound LNP23 on MCF-7 cells was investigated, including protein expression of p-PI3K and p-AKT by Western blot assay, AO/EB staining assay, hoechst33342 assay, cell apoptosis assays by flow cytometry, cell cycle analysis by flow cytometry, clone formation assay and transwell migration assay. Additionally, the preliminary SARs of these compounds were also discussed.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110333"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786300","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}

{"title":"Hybrid design reveals a dopamine D3R ligand with promising in vitro ADME properties.","authors":"Hari K Namballa, Michael Dorogan, Sandip Patra, Ashok Gudipally, Li Xie, Lei Xie, Wayne W Harding","doi":"10.1016/j.bioorg.2026.110432","DOIUrl":"10.1016/j.bioorg.2026.110432","url":null,"abstract":"<p><p>There is significant interest in identifying dopamine D3 receptor (D3R) antagonists and partial agonists with favorable drug-like properties as in vivo chemical tools and as experimental therapeutics for substance use disorders. We hypothesized that preserving the classical D3R antagonist pharmacophore while incorporating metabolically favorable structural features into the secondary pharmacophore (\"tail\") region would enable the discovery of selective D3R-targeted ligands with good ADME characteristics. Specifically, orthosteric binding site (\"head\") fragments known to confer D3R affinity were coupled with \"tail\" motifs inspired by non-catechol D1 receptor agonists, which have demonstrated enhanced pharmacokinetic stability. From this work, we have identified a new D3R ligand compound 8o. Compound 8o exhibits high affinity for D3R (2.7 nM) with >30-fold binding preference versus other dopamine receptors. Preliminary functional activity studies suggest that compound 8o is a D3R partial agonist. Docking studies indicate that 8o exhibits D3R interactions that are consistent with a bitopic mode of binding. Compound 8o also shows favorable in vitro ADME properties, that are predictive of good drug-like behavior, making it a promising lead molecule for future D3R in vivo probe and therapeutic optimization.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"181 ","pages":"110432"},"PeriodicalIF":5.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}