European Journal of Medicinal Chemistry Reports最新文献_第3页

Aurones as versatile enzyme Inhibitors: Recent advancements, structural insights, mechanisms, and therapeutic potential 作为多功能酶抑制剂的Aurones：最新进展，结构见解，机制和治疗潜力

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-06-11 DOI: 10.1016/j.ejmcr.2025.100280

Bhavna Saroha , Gourav Kumar , Suresh Kumar

Aurones belong to the flavonoid-based heterocyclic class of plant origin and are full of therapeutic potential. Characterized by their unique benzofuranone core structure and α,β unsaturated carbonyl group, aurones possess exceptional structural adaptability and electronic characteristics, making them excellent candidates for enzyme targeting and promising agents for drug development. Recent research has highlighted their ability to inhibit key enzymes, including cholinesterase, cathepsin B, monoamine oxidase, cyclooxygenase, and various digestive enzymes. This demonstrates their potential in treating cancer, neurodegenerative diseases, and metabolic disorders associated with the overexpression of these enzymes. The ability to functionalize the aurone scaffold further enhances its adaptability for selective and potent enzyme targeting. This review examines the structural features of aurones, their enzyme-inhibitory effects, an overview of their molecular mechanisms, and the structure-activity relationships (SAR) underlying their enzyme inhibition, supported by computational approaches. Although several review articles have addressed the synthetic and general biological profile of aurones, none have specifically focused on their enzyme inhibitory potential, which is the central theme of this review. This review offers a strong foundation and rationale for the design, synthesis, and optimization of novel aurone-based compounds aimed at achieving desirable therapeutic outcomes by targeting specific enzymes.

金酮属植物来源的类黄酮类杂环化合物，具有广阔的治疗潜力。aurones具有独特的苯并呋喃酮核心结构和α，β不饱和羰基，具有良好的结构适应性和电子特性，是酶靶向和药物开发的理想候选者。最近的研究强调了它们抑制关键酶的能力，包括胆碱酯酶、组织蛋白酶B、单胺氧化酶、环氧合酶和各种消化酶。这证明了它们在治疗癌症、神经退行性疾病和与这些酶过表达相关的代谢紊乱方面的潜力。aurone支架的功能化能力进一步增强了其选择性和强效酶靶向的适应性。本文综述了aurones的结构特征，它们的酶抑制作用，概述了它们的分子机制，以及它们的酶抑制背后的构效关系（SAR），并以计算方法为支持。虽然有几篇综述文章讨论了aurones的合成和一般生物学概况，但没有一篇特别关注它们的酶抑制潜力，这是本文的中心主题。这一综述为设计、合成和优化新的基于auron的化合物提供了坚实的基础和理论依据，这些化合物旨在通过靶向特定的酶来达到理想的治疗效果。

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引用次数: 0

Molecules with alkyne fragment in medicinal chemistry: The path from neurotoxins to drugs 药物化学中的炔片段分子：从神经毒素到药物的途径

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-08-18 DOI: 10.1016/j.ejmcr.2025.100294

Nataliya Zelisko , Roman Lesyk

In this comprehensive review, we explore a diverse array of highly promising compounds, categorized based on their pharmacological properties, origins, and synthetic methodologies, to highlight the critical role of alkyne functionalities in advancing medicinal chemistry. Our analysis underscores the unique contributions of acetylene-containing compounds, emphasizing their structural significance and therapeutic potential.

The remarkable versatility of acetylene-bearing molecules is evident in their wide-ranging biological activities, which position them as exceptional candidates for drug development. Extensive studies compiled in this review demonstrate that incorporating an acetylene group into molecular frameworks significantly enhances bioactivity. Numerous naturally occurring alkynes exhibit potent antibacterial, antifungal, and anticancer effects. Notably, compounds featuring a propargylamine group are established inhibitors of monoamine oxidase (MAO) and cholinesterases (ChEs). Additionally, a range of alkyne derivatives shows promise as H3-receptor antagonists, offering potential treatments for conditions such as epilepsy, depression, schizophrenia, Parkinson's disease, Alzheimer's disease, sleep disorders, attention deficit hyperactivity disorder, and various inflammatory and gastrointestinal disorders. Acetylene-containing compounds also play a role in anti-HIV therapies, with certain synthetic steroids falling within this class. Furthermore, alkynes are integral to multi-target-directed ligand (MTDL) strategies, broadening their therapeutic applications.

A particular focus of this review is the compelling anticancer potential of MAO inhibitors, which have garnered significant attention from pharmaceutical companies for their efficacy against prostate cancer, Hodgkin lymphoma, glioma brain tumors, non-small cell lung cancer, A-2058 melanoma cell lines, and acute myeloid leukemia. This has spurred interest in drug repurposing, establishing these compounds as a cornerstone of innovative therapeutic development.

在这篇全面的综述中，我们根据其药理性质、来源和合成方法对各种极具前景的化合物进行了分类，以突出炔官能团在推进药物化学中的关键作用。我们的分析强调了含乙炔化合物的独特贡献，强调了它们的结构意义和治疗潜力。含乙炔分子的显著多功能性在其广泛的生物活性中是显而易见的，这使它们成为药物开发的特殊候选者。大量的研究表明，在分子框架中加入乙炔基团可以显著提高生物活性。许多天然存在的炔具有强大的抗菌、抗真菌和抗癌作用。值得注意的是，含有丙胺基团的化合物是单胺氧化酶（MAO）和胆碱酯酶（ChEs）的抑制剂。此外，一系列炔衍生物显示出作为h3受体拮抗剂的前景，为癫痫、抑郁症、精神分裂症、帕金森病、阿尔茨海默病、睡眠障碍、注意缺陷多动障碍以及各种炎症和胃肠道疾病等疾病提供潜在的治疗方法。含乙炔的化合物也在抗hiv治疗中发挥作用，某些合成类固醇就属于这一类。此外，炔烃是多靶点定向配体（MTDL）策略的组成部分，扩大了它们的治疗应用。本综述的一个特别重点是MAO抑制剂的抗癌潜力，由于其对前列腺癌、霍奇金淋巴瘤、胶质瘤脑肿瘤、非小细胞肺癌、A-2058黑色素瘤细胞系和急性髓性白血病的疗效，引起了制药公司的极大关注。这激发了人们对药物再利用的兴趣，使这些化合物成为创新治疗发展的基石。

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引用次数: 0

Towards "unmakable" psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy 走向“不可制造”的致幻剂：通过hatu介导的酰胺偶联策略获得的裸叶皂苷类似物的SAR探索

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-06-03 DOI: 10.1016/j.ejmcr.2025.100278

Judith Stirn , Raphael Berger , Harald Hübner , Peter Gmeiner , Christian D. Klein

4-Hydroxytryptamines such as psilocin and its prodrug psilocybin are of considerable current interest for innovative antidepressant and other neuropsychiatric treatments. We here present a synthetic route towards 4-hydroxytryptamines displaying a high versatility for SAR exploration at the aliphatic nitrogen. The core concept is to apply HATU-mediated amide couplings to a readily accessible and stable N¹-Boc-indole-3-glyoxylic acid precursor followed by N-deprotection under mild conditions. We illustrate the versatility of this approach by the synthesis of various sterically hindered, conformationally constrained, chiral, and electron-deficient 4-hydroxytryptamines, including closely related congeners of iprocin. In addition, the structure-activity relationships of the obtained compounds are explored with a focus on their interaction with the serotonin receptors 1A and 2A (5-HT_1/2A). An increase in steric bulk at the aliphatic nitrogen appears to be detrimental to the affinity to the 5-HT_2A receptor, whereas azetidinyl tryptamines bearing a terminal aryl moiety demonstrated remarkably high affinity.

4-羟色胺，如裸盖菇素及其前药裸盖菇素，是目前创新抗抑郁药和其他神经精神治疗的重要兴趣。我们在这里提出了一种合成4-羟色胺的方法，在脂肪族氮的SAR探测中具有很高的通用性。核心概念是将hatu介导的酰胺偶联应用于易于获得且稳定的n1 - boc -吲哚-3-乙醛酸前体，然后在温和条件下进行n -脱保护。我们通过合成各种位阻、构象约束、手性和缺电子的4-羟色胺来说明这种方法的多功能性，包括与异丙酸密切相关的同族物质。此外，我们还探索了所获得化合物的构效关系，重点研究了它们与5-羟色胺受体1A和2A （5-HT1/2A）的相互作用。脂肪族氮的空间体积增加似乎不利于与5-HT2A受体的亲和力，而带有末端芳基片段的氮杂二基色胺则表现出显著的高亲和力。

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引用次数: 0

Structure optimization at position five of 4-thiazolidinone resulted in new potent PIM1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities for combating colorectal cancer 4-噻唑烷酮第5位的结构优化得到了新的有效的PIM1激酶抑制剂，具有诱导凋亡和激活caspase 3/7的能力，可用于对抗结直肠癌

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-06-04 DOI: 10.1016/j.ejmcr.2025.100279

Ahmed K. Al-Kubeisi , Saad R. El-Zemity , Marwa M. Abu-Serie , Aly A. Hazzaa , Mostafa M.M. El-Miligy

New thymol – 5-phenylthiazolidin-4-one hybrids were synthesized aiming to interact with the lipophilic flexible p-loop of PIM kinase active site via induced-fit binding mode to increase affinity hence anticancer activity against colorectal cancer (CRC). All target compounds were screened for their cytotoxicity against normal human lung fibroblasts and anticancer activity against CRC Caco-2 cell lines. 6c and 6e exhibited the highest anticancer activity at doses less than their EC₁₀₀ on normal human cells. In addition, 6c and 6e were further tested against liver cancer cell line (HepG-2) and breast cancer cell line (MCF-7) and proved their potent anticancer activities. Furthermore, both induced apoptosis in Caco-2 cell lines by 39 and 55 % and enhanced caspase 3/7 activation by 43 and 65 %, respectively. Besides, 6c and 6e revealed in vitro inhibitory activity against PIM1 kinase more than PIM2 kinase. Furthermore, induced fit docking and molecular dynamics simulation of 6c and 6e predicted enhanced PIM1 kinase activity via interaction to flexible p-loop. Moreover, both could act as PIM1 kinase competitive non-ATP mimetics as they interacted with Lys67.

合成了新的百里酚- 5-苯基噻唑烷-4- 1杂合体，目的是通过诱导配合结合模式与PIM激酶活性位点的亲脂性柔性p环相互作用，提高亲和力，从而提高抗结直肠癌的活性。所有目标化合物对正常人肺成纤维细胞的细胞毒性和对CRC Caco-2细胞系的抗癌活性进行了筛选。6c和6e在低于EC100的剂量下对正常人体细胞表现出最高的抗癌活性。此外，6c和6e还对肝癌细胞株HepG-2和乳腺癌细胞株MCF-7进行了进一步的抗肿瘤实验，证实了它们具有较强的抗肿瘤活性。此外，两者对Caco-2细胞株的诱导凋亡率分别为39%和55%，对caspase 3/7的激活率分别为43%和65%。此外，6c和6e对PIM1激酶的体外抑制活性高于PIM2激酶。此外，6c和6e的诱导配合对接和分子动力学模拟预测了PIM1激酶活性通过与柔性p环的相互作用增强。此外，两者都可以作为PIM1激酶竞争的非atp模拟物与Lys67相互作用。

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引用次数: 0

Halogen-containing NHC and bis-NHC silver complexes. Synthesis, structure and antimicrobial activity 含卤NHC和双NHC银配合物。合成、结构和抗菌活性

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-09-23 DOI: 10.1016/j.ejmcr.2025.100298

Alexandr S. Avksentiev , Vagiz Sh Saberov , Svetlana V. Shishkina , Alexey B. Ryabitsky , Olena Z. Komarovska-Porokhnyavets , Vira I. Lubenets , Vitaliy A. Matvienko , Gennady F. Rayenko , Liubov M. Vakhitova , Nikolai I. Korotkikh

It was found that the in-situ reaction of halogen-containing imidazolium and benzimidazolium salts with silver nitrate, chloride, iodide or perchlorate in the presence of potassium carbonate leads to the corresponding monocarbene (NHC) (LAgX) and bis-NHC silver complexes (L₂AgX) including the first strongly sterically shielded bis-NHC complexes (IPr)₂AgX. In the presence of o-phenanthroline, carbene-phenanthroline complex (IPr∗)(phen)AgClO₄ was obtained. The reactions can be an addition to the known method of Lin with the use of silver oxide. The halogenide silver carbene complexes are also obtained by the exchange of the anion from the ionic perchlorate complexes to halogenide ions (Cl⁻, I⁻). The structure of the synthesized compounds is confirmed by the methods of ¹H and ¹³C NMR spectroscopy and for five compounds by the X-ray diffraction study. Most compounds have an ionic character in crystals and in solutions, even for the complex with a sterically shielded silver atom (IPr)₂AgNO₃ and monocarbene complexes. Synthesized complexes show high antibacterial (MIC up to 1.9 μg/mL on M. luteum) and antifungal activity (MIC up to 0.9 μg/mL on A. niger and 1.9 μg/mL on C. tenuis).

研究发现，含卤咪唑和苯并咪唑盐在碳酸钾存在下与硝酸银、氯化物、碘化物或高氯酸盐原位反应可生成相应的单碳（NHC）（LAgX）和双NHC银配合物（L2AgX），其中包括首个强空间屏蔽的双NHC配合物（IPr）2AgX。在邻菲罗啉存在下，得到了卡宾-菲罗啉配合物（IPr∗）（phen）AgClO4。这些反应可以作为已知的Lin方法的补充，使用氧化银。通过离子高氯酸盐配合物中的阴离子交换卤化物离子（Cl−,I−），也可以得到卤化银碳配合物。合成化合物的结构通过1H和13C核磁共振谱法和x射线衍射研究得到证实。大多数化合物在晶体和溶液中都具有离子性质，甚至对于具有空间屏蔽银原子（IPr）的配合物（2AgNO3）和单羰基配合物也是如此。合成的配合物具有较高的抑菌活性（对黄体霉的MIC可达1.9 μg/mL）和抗真菌活性（对黑曲霉的MIC可达0.9 μg/mL，对黄曲霉的MIC可达1.9 μg/mL）。

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引用次数: 0

Research progress of sustained-release microsphere technology in drug delivery 缓释微球技术在给药中的研究进展

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-09-26 DOI: 10.1016/j.ejmcr.2025.100299

Tao-Tao Ge, Hai-Yan Guo, Chun-Mei Zhang, Shu-Feng Li

sustained-release microsphere technology, with its unique advantages of prolonged controlled release, enhanced therapeutic efficacy, reduced side effects, and improved patient compliance, has emerged as a research hotspot in modern drug delivery. This review systematically summarizes recent advances in sustained-release microspheres in the biomedical field. First, the core concepts and distinct advantages of this approach, compared with conventional drug administration, are elaborated. Subsequently, the principles and features of key preparation techniques, including emulsion–solvent evaporation, spray drying, and advanced microfluidic methods, are highlighted. Furthermore, the applications and validation of microsphere-based systems in diverse therapeutic areas—such as transarterial chemoembolization for cancer, chronic disease management (e.g., diabetes, psychiatric disorders), and local targeted therapies (e.g., ophthalmology, postoperative analgesia)—are critically discussed. Finally, the current challenges and future perspectives of this technology are outlined, providing insights for its further development and clinical translation.

缓释微球技术以其缓释时间延长、疗效提高、副作用减少、患者依从性提高等独特优势，成为现代给药领域的研究热点。本文系统综述了近年来缓释微球在生物医学领域的研究进展。首先，阐述了该方法相对于传统给药方式的核心概念和明显优势。随后，重点介绍了乳液-溶剂蒸发、喷雾干燥、先进微流控等关键制备技术的原理和特点。此外，微球系统在不同治疗领域的应用和验证——如经动脉化疗栓塞治疗癌症、慢性疾病管理（如糖尿病、精神疾病）和局部靶向治疗（如眼科、术后镇痛）——也进行了批判性的讨论。最后，概述了该技术目前面临的挑战和未来的前景，为其进一步发展和临床转化提供了见解。

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引用次数: 0

Glaucumolides C-P, cembrane-type diterpenoids from the marine soft coral Sarcophyton glaucum with potential attenuating activities against IgAN nephropathy 来自海洋软珊瑚青光石的膜型二萜类化合物C-P对IgAN肾病具有潜在的减弱作用

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-07-25 DOI: 10.1016/j.ejmcr.2025.100287

Kang Zhou , Jian Huang , Hongli Jia , Pianpian Wang , Bin Wang , Wei Cheng , Wenhan Lin

Cembranoids represent a class of diterpenes, featuring a cyclotetradecadiene backbone substituted by an isopropyl residue and three methyl groups with diverse subtypes and a panel of bioactivities. In this study, molecular networking-based metabolomic analysis revealed the soft coral Sarcophyton glaucum containing a chemical profile of cembrane-type diterpenes. Targeted isolation of the diterpene-enriched fractions resulted in the isolation of 14 undescribed cembranoids, namely glaucumolides C-P (1–14). Their structures were determined by extensive spectroscopic data in association with the X-ray diffraction and electronic circular dichroism (ECD) data for configurational assignments. All analogs featured an unsaturated γ-lactone in the backbone. Glaucumolide M and metabolite-A exhibited significant inhibition against the proliferation of lipopolysaccharide (LPS)-induced DAKIKI cells, and upregulated the expression of mRNA of C1GalT1 and its chaperone Cosmc in DAKIKI cells dose-dependently. Those findings suggest glaucumolides to be potential to prevent imunoglobulin A (IgA) nephropathy.

类cembranoid是一类二萜化合物，具有一个环十四二烯主链被一个异丙基残基取代，三个甲基具有不同的亚型和一组生物活性。在这项研究中，基于分子网络的代谢组学分析揭示了软珊瑚Sarcophyton glaucum含有膜型二萜的化学特征。对富含二萜的组分进行定向分离，分离出14种未描述的膜类化合物，即青绿毛酸酯C-P（1-14）。它们的结构是通过大量的光谱数据，结合x射线衍射和电子圆二色性（ECD）数据来确定的。所有类似物的主链中都含有不饱和γ-内酯。青苔内酯M和代谢产物a对脂多糖（LPS）诱导的DAKIKI细胞增殖有显著抑制作用，并呈剂量依赖性上调DAKIKI细胞中C1GalT1及其伴侣蛋白Cosmc mRNA的表达。这些发现表明青铜绿内酯具有预防免疫球蛋白A （IgA）肾病的潜力。

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引用次数: 0

New promising transthyretin stabilizers for cardiac amyloidosis treatment 治疗心脏淀粉样变性的新有前途的转甲状腺素稳定剂

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-11-01 DOI: 10.1016/j.ejmcr.2025.100308

Lidia Ciccone , Caterina Camodeca , Carole Fruchart-Gaillard , Robert Thaï , Nicolò Tonali , Giuseppina Basta , Serena Del Turco , Lara Russo , Magali Noiray , Serena Sirigu , William Shepard , Lucia Barlettani , Francesco Mazzocchi , Elisabetta Orlandini , Susanna Nencetti

Transthyretin (TTR) is a plasma protein responsible for transport of thyroxine and retinol, the latter through binding with the retinol-binding protein. In contrast with its physiological role, TTR possesses an intrinsic amyloidogenic potential due to the high content of β-strands. Under pathological conditions, TTR undergoes a misfolding process forming protein aggregates and fibrils that cause organ damage and dysfunction, leading to the onset of TTR amyloidosis diseases (ATTRs). One therapeutic approach against ATTRs progression involves administering small molecules able to bind the inner channel of the protein enhancing tetramer stability. Here, we report the synthesis and characterization of 2-(((benzyloxy)imino)methyl)benzoic acids (1a-l), 3-(((benzyloxy)imino)methyl)benzoic acids (2a-l) and 4-(((benzyloxy)imino)methyl)benzoic acids (3a-l) as new potential inhibitors of TTR fibril formation. Our study shows that compounds 1a ((E)-2-((((2-(trifluoromethyl)benzyl)oxy)imino)methyl)benzoic acid)), 1d ((E)-2-((((2-chlorobenzyl)oxy)imino)methyl)benzoic acid), 2l ((E)-3-((((2-chloro-6-fluorobenzyl)oxy)imino)methyl)benzoic acid) and 3g ((E)-4-((((2-methoxybenzyl)oxy)imino)methyl)benzoic acid) effectively inhibit the aggregation of wild-type TTR (wt-TTR) and mutants (V30M, V122I). Among these derivatives 1a and 1d have stronger ability to contrast the fibril formations. The binding affinity of 1a, 1d, 2l with TTR (wt, V30M and V122I) was determined by fluorescence displacement assay and isothermal titration calorimetry. The binding modes of the selected ligands have been confirmed by X-ray crystallography. Moreover, these compounds show no toxicity in endothelial and cardiomyocyte cells, reinforcing their potential as TTR stabilizers.

转甲状腺素（TTR）是一种血浆蛋白，负责甲状腺素和视黄醇的运输，后者通过与视黄醇结合蛋白结合。与其生理作用相反，由于β-链的高含量，TTR具有内在的淀粉样蛋白形成潜能。在病理条件下，TTR发生错误折叠过程，形成蛋白聚集体和原纤维，导致器官损伤和功能障碍，导致TTR淀粉样变性病（ATTRs）的发病。针对ATTRs进展的一种治疗方法是给予能够结合蛋白质内部通道的小分子，增强四聚体的稳定性。本文报道了2-（（苯氧基）亚胺基）甲基苯甲酸（1a-l）、3-（（苯氧基）亚胺基）甲基苯甲酸（2a-l）和4-（（苯氧基）亚胺基）甲基苯甲酸（3a-l）作为TTR纤维形成新的潜在抑制剂的合成和表征。我们的研究表明，化合物1a ((E)-2-（（（（2-（三氟甲基）苄基）氧（亚胺）甲基）苯甲酸））、1d ((E)-2-(（（（2-氯苯基）氧（亚胺）甲基）苯甲酸）、2l ((E)-3-(（（（2-氯-6-氟苯基）氧（亚胺）甲基）苯甲酸）和3g ((E)-4-(（（（2-甲氧基苄基）氧（亚胺）甲基）苯甲酸）能有效抑制野生型TTR （wt-TTR）和突变体（V30M, V122I）的聚集。其中1a和1d对原纤维形成的对比能力较强。用荧光位移法和等温滴定量热法测定了1a、1d、2l与TTR （wt、V30M和V122I）的结合亲和力。所选配体的结合模式已被x射线晶体学证实。此外，这些化合物对内皮细胞和心肌细胞没有毒性，增强了它们作为TTR稳定剂的潜力。

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引用次数: 0

Regulation of mitochondrial potassium BKCa channel by naringenin derivatives: application of a new cellular model 柚皮素衍生物对线粒体BKCa钾通道的调控：一种新的细胞模型的应用

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-10-22 DOI: 10.1016/j.ejmcr.2025.100304

Aleksandra Sęk , Silvia Cammarone , Rafał P. Kampa , Karolina Pytlak , Barbara Kalenik , Joanna Lewandowska , Francesca Ghirga , Isabella Romeo , Omar Atrooz , Piotr Bednarczyk , Adam Szewczyk , Bruno Botta , Deborah Quaglio , Bogusz Kulawiak

Mitochondrial potassium (mitoK) channels play a crucial role in mitochondrial and cellular physiology. One of the best described mitoK channels is the mitochondrial large-conductance calcium-activated potassium (mitoBK_Ca) channel. It has been shown that activation of the mitoBK_Ca channel protects the heart and brain tissue against ischemia/reperfusion injury. This channel may be formed in mitochondria by the VEDEC isoform of the α subunit encoded by the KCNMA1 gene. In addition to regulation by canonical channel blockers and potassium channel openers, this channel is regulated by flavonoids, including naringenin. Our work aimed to establish and use a new cellular model to investigate the role of new naringenin derivatives in regulating the activity of the mitoBK_Ca channel. We developed HEK293 cells stably expressing the VEDEC isoform of the BK_Ca (HEK293-BK_DEC). Using the patch-clamp technique on isolated mitoplasts from the newly established cell line, we detected the activity of a potassium channel exhibiting all the characteristics of the mitoBK_Ca channel, such as a conductance of 289 pS, voltage-dependent changes in opening probability, channel activation by calcium ions, and inhibition by paxilline. Additionally, introducing the VEDEC isoform into HEK293 cells led to an increase in the mitochondrial oxygen consumption rate and a change in the expression of certain genes encoding mitochondrial proteins involved in oxidative phosphorylation. Subsequently, we investigated the influence of new naringenin derivatives on the activity of the mitoBK_Ca channel. We observed that depending on the type of modification of this flavonoid, the channel could be activated or inhibited by the tested naringenin derivatives. In summary, we have developed a new experimental model enabling the study of mitoK channel activity with a defined molecular structure exemplified by the mitoBK_Ca channel. This model can be used to test new modulators of the mitochondrial potassium channels, which could be employed for further physiological studies in the future.

线粒体钾离子通道在线粒体和细胞生理中起着至关重要的作用。其中一个描述最好的mitoK通道是线粒体大电导钙活化钾（mitoBKCa）通道。研究表明，激活mitoBKCa通道可以保护心脏和脑组织免受缺血/再灌注损伤。这个通道可能是由KCNMA1基因编码的α亚基的VEDEC亚型在线粒体中形成的。除了典型通道阻滞剂和钾通道开放剂的调节外，该通道还受类黄酮（包括柚皮素）的调节。我们的工作旨在建立和使用一个新的细胞模型来研究新的柚皮素衍生物在调节mitoBKCa通道活性中的作用。我们培育了稳定表达BKCa VEDEC亚型（HEK293- bk_dec）的HEK293细胞。利用膜片钳技术对新建立的细胞系分离的有丝分裂体进行检测，我们检测到钾通道的活性表现出mitoBKCa通道的所有特征，如289 pS的电导、电压依赖性的打开概率变化、钙离子激活通道和paxilline抑制通道。此外，将VEDEC异构体引入HEK293细胞会导致线粒体耗氧量增加，并改变编码线粒体氧化磷酸化蛋白的某些基因的表达。随后，我们研究了新的柚皮素衍生物对mitoBKCa通道活性的影响。我们观察到，柚皮素衍生物对该通道的激活或抑制作用取决于该类黄酮的修饰类型。总之，我们已经开发了一种新的实验模型，能够研究mitoK通道活性与mitoBKCa通道为例的确定的分子结构。该模型可用于测试线粒体钾通道的新调节剂，可用于未来进一步的生理研究。

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引用次数: 0

Dual-target candidate compounds from a transformer chemical language model contain characteristic structural features 从变压器化学语言模型的双目标候选化合物包含特征的结构特征

European Journal of Medicinal Chemistry Reports

Pub Date : 2025-12-01 Epub Date: 2025-07-30 DOI: 10.1016/j.ejmcr.2025.100291

Sanjana Srinivasan , Alec Lamens , Jürgen Bajorath

Chemical language models (CLMs) are increasingly used for generative design of candidate compounds for medicinal chemistry. However, their predictions are difficult to rationalize. Currently, detailed computational explanations of CLM-based compound generation are unavailable. Therefore, we have attempted to better understand from a medicinal chemistry perspective how CLMs learn and arrive at compound predictions. Therefore, we have subjected dual-target candidate compounds for polypharmacology generated with transformer CLMs to a series of analysis steps exploring structural features that are learned and compared them to known compounds with dual-target activity. Using machine learning combined with distinct chemical structure-oriented approaches from explainable artificial intelligence, we show that CLMs learn substructures characteristic of known dual-target compounds as a basis for generating new candidates with various chemical modifications.

化学语言模型（CLMs）越来越多地用于药物化学候选化合物的生成设计。然而，他们的预测很难合理化。目前，还没有基于clm的化合物生成的详细计算解释。因此，我们试图从药物化学的角度更好地理解clm是如何学习和达到化合物预测的。因此，我们对由变压器CLMs生成的多药理学的双靶点候选化合物进行了一系列分析步骤，探索所了解的结构特征，并将它们与具有双靶点活性的已知化合物进行比较。利用机器学习与可解释人工智能的不同化学结构导向方法相结合，我们表明clm学习已知双靶化合物的亚结构特征，作为生成具有各种化学修饰的新候选化合物的基础。

引用次数: 0