Bioorganic & Medicinal Chemistry Letters最新文献_第8页

Iridium and rhenium complexes in photodynamic and sonodynamic therapy: mechanistic insights and therapeutic potential 光动力和声动力治疗中的铱和铼配合物：机理见解和治疗潜力。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-24 DOI: 10.1016/j.bmcl.2025.130479

Sreejani Ghosh , Rinku Chakrabarty , Priyankar Paira

Cancer maintains to be a major worldwide health epidemic, and despite breakthroughs in targeted agents, immunotherapy, chemotherapy, and surgery, considerable limitations persist. These comprise therapeutic resistance, dose-limiting toxicities, late diagnosis, and microenvironmental barriers, including hypoxia and poor perfusion. The spatiotemporally regulated, locally activated cytotoxicity that photodynamic therapy (PDT) and sonodynamic therapy (SDT) provide has made them appealing substitutes. They may also be used in conjunction with immunotherapy and imaging. SDT uses ultrasound to allow for deeper penetration and partial oxygen independence, whereas PDT uses light to activate photosensitisers. Both approaches produce radical intermediates and reactive oxygen species (ROS), which harm vital biomolecules and activate several pathways leading to programmed cell death, hence decreasing the probability of resistance. However, SDT necessitates the optimisation of acoustic parameters and verified clinical protocols, while PDT is limited by oxygen reliance and poor light penetration. Transition metal complexes, especially those of iridium (III) and rhenium (I), offer special benefits for PDT and SDT because of their intrinsic luminescence, effective triplet-state creation, high spin–orbit coupling, and variable photophysical characteristics. Their translational potential is being advanced by rational design tactics such as theranostic pairing, red/NIR and two-photon activation, nanocarrier integration, and Type I biasing for hypoxia tolerance. With continuous attempts to standardise dosimetry and sensitiser design, SDT is still in the early phases of evaluation, whereas PDT is clinically established. This study highlights Ir and Re complexes as adaptable next-generation sensitisers that could broaden the therapeutic reach of externally activated cancer medicines by synthesising molecular insights, representative chemical classes, and translational obstacles.

癌症仍然是世界范围内主要的健康流行病，尽管在靶向药物、免疫疗法、化疗和手术方面取得了突破，但仍存在相当大的局限性。这些障碍包括治疗耐药性、剂量限制性毒性、晚期诊断和微环境障碍，包括缺氧和灌注不良。光动力疗法（PDT）和声动力疗法（SDT）提供的时空调节、局部激活的细胞毒性使它们成为有吸引力的替代品。它们也可以与免疫疗法和成像结合使用。SDT使用超声波允许更深的穿透和部分氧不依赖性，而PDT使用光来激活光敏剂。这两种方法都会产生自由基中间体和活性氧（ROS），它们会损害重要的生物分子，并激活几种导致程序性细胞死亡的途径，从而降低耐药性的可能性。然而，SDT需要优化声学参数和经过验证的临床方案，而PDT则受氧气依赖和光线穿透性差的限制。过渡金属配合物，特别是铱（III）和铼(I)的配合物，由于其固有的发光，有效的三重态产生，高自旋轨道耦合和可变的光物理特性，为PDT和SDT提供了特殊的好处。通过合理的设计策略，如治疗配对、红/近红外和双光子激活、纳米载流子集成和I型耐缺氧偏置，它们的转化潜力正在提高。随着对剂量学和致敏剂设计标准化的不断尝试，SDT仍处于评估的早期阶段，而PDT已在临床建立。这项研究强调了Ir和Re复合物作为适应性强的下一代增敏剂，可以通过合成分子见解，代表性化学类别和翻译障碍来扩大外部激活癌症药物的治疗范围。

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引用次数: 0

LXH254 hybrid with adamantane: synthesis and in vitro evaluation of 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety as a novel B-RAF inhibitor 金刚烷- LXH254杂化物：含金刚烷基的2,4,6-三取代吡啶衍生物Z-001的合成及体外评价

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-21 DOI: 10.1016/j.bmcl.2025.130481

Wei Fan , Meina Li , Yeming Wang

In this study, 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety was designed through the hybridization strategy of LXH254 and adamantane. A new and effective synthetic route was established to achieve the synthesis of Z-001 through four step reactions, starting from commercially available 3-bromo-4-methylaniline and (2,6-dichloropyridin-4-yl) boronic acid. Besides, Z-001 was evaluated inhibitory activity against B-RAF kinase with IC₅₀ value of 37.80 nM by ADP-Glo kinase assay, and it was found that Z-001 was a more potent B-RAF inhibitor than Vemurafinib (IC₅₀ = 78.52 nM). Furthermore, molecular docking simulations showed that Z-001 bound to DFG-out/C-helix-in conformation in the B-RAF kinase, and formed three hydrogen bonds with GLU501, ASP594 and CYS532, respectively. It was worth noting that the adamantane alcohol of Z-001 was very suitable for matching the cavities near the solvent exposed region, which was filled with adamantyl moiety and effectively utilized in the docking model. The binding mode between Z-001 and B-RAF kinase provided a reasonable explanation for Z-001 as a potential B-RAF kinase inhibitor.

本研究通过LXH254与金刚烷的杂化策略，设计了含有金刚烷片段的2,4,6-三取代吡啶衍生物Z-001。以市售的3-溴-4-甲基苯胺和（2,6-二氯吡啶-4-基）硼酸为原料，通过四步反应合成了Z-001。此外，通过ADP-Glo激酶试验评估Z-001对B-RAF激酶的抑制活性，IC50值为37.80 nM，发现Z-001比Vemurafinib更有效（IC50 = 78.52 nM）。此外，分子对接模拟表明，Z-001在B-RAF激酶中结合到DFG-out/ c -螺旋-in构象，并分别与GLU501、ASP594和CYS532形成3个氢键。值得注意的是，Z-001的金刚烷醇非常适合匹配溶剂暴露区附近的空腔，其中充满金刚烷基部分，在对接模型中得到了有效的利用。Z-001与B-RAF激酶的结合模式为Z-001作为潜在的B-RAF激酶抑制剂提供了合理的解释。

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引用次数: 0

Chemiluminescent probes for imaging cysteine cathepsin activity 半胱氨酸组织蛋白酶活性成像的化学发光探针。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-20 DOI: 10.1016/j.bmcl.2025.130480

Jiyun Zhu , Sara Gutkin , Shiyu Chen , Shih-Po Su , Hai Phan , Doron Shabat , Matthew Bogyo

The cysteine cathepsins are a family of proteases that are widely expressed in diverse cell types. However, because their activity is highly upregulated at sites of inflammation, they are ideal targets for imaging a range of disease pathologies including cancer, atherosclerosis, fibrosis and others. While significant advances have been made in generation of activatable ‘smart’ probes for cathepsin activity, virtually all of these agents use fluorescent reporters which require a laser light source to induce a signal from the probe. We describe here the development and application of chemiluminescent probes for imaging cysteine cathepsin activity in cells and tissues. These probes provide rapid signal generation with low background in cells and tissues without the need for a light source. We demonstrate that a cathepsin probe containing an optimal peptide sequence can be used topically to detect activity in tumor tissues, demonstrating the potential value of this approach for real-time diagnosis of cancer as well as other conditions involving inflammation.

半胱氨酸组织蛋白酶是在多种细胞类型中广泛表达的蛋白酶家族。然而，由于它们的活性在炎症部位高度上调，它们是一系列疾病病理成像的理想靶点，包括癌症、动脉粥样硬化、纤维化等。虽然在组织蛋白酶活性的可激活“智能”探针的产生方面取得了重大进展，但实际上所有这些试剂都使用荧光报告，这需要激光光源来诱导探针发出信号。我们在这里描述了化学发光探针成像细胞和组织中半胱氨酸组织蛋白酶活性的发展和应用。这些探针在细胞和组织中提供低背景的快速信号产生，而不需要光源。我们证明了包含最佳肽序列的组织蛋白酶探针可以局部用于检测肿瘤组织中的活性，证明了这种方法在实时诊断癌症以及其他涉及炎症的疾病方面的潜在价值。

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引用次数: 0

Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor 基于片段的药物发现策略发现DS79540454：缺氧诱导因子脯氨酸羟化酶抑制剂的新支架。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-19 DOI: 10.1016/j.bmcl.2025.130476

Takeshi Fukuda, Tatsuya Nishi, Takashi Ishiyama, Ryoko Kitazawa, Ken Ishii, Shinichi Takahashi, Yuki Kawabata, Kyoji Yamaguchi, Daichi Baba, Shuichiro Ito, Naoki Tanaka

The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.

抑制缺氧诱导因子脯氨酸羟化酶结构域蛋白（hif - phd）是治疗肾性贫血的一种很有前途的策略。我们基于基于片段的药物发现策略，利用HIF-PHD2结构域与化合物配合物的各种x射线晶体结构，鉴定出具有HIF-PHD抑制活性的羟基嘧啶核心。我们结合晶体结构上的结构信息，与6-乙酰胺烟酸络合，发现了全新的氨基琥珀酸支架。DS79540454具有与DS-1093a相当的高酶抑制活性，已进入临床试验阶段。

引用次数: 0

Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease 白术烯内酯的结构修饰：具有抗a β聚集和抗阿尔茨海默病神经保护活性的衍生物的合成和评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-18 DOI: 10.1016/j.bmcl.2025.130478

Tiancheng Sun , Zhonghua Li , Bingyu Xiao , Jige Yang , Mengyu Han , Jiaxin Zhang , Sijia Liu , Jinlian Ma , Pan Wang

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like Atractylodes macrocephala (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu²⁺-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy

阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是β-淀粉样蛋白（a β）沉积、过度磷酸化的Tau缠结和神经元丢失，缺乏有效的疾病改善疗法。由于其结构多样性和神经保护潜力，像苍术（AM）这样的草药为阿尔茨海默病药物的开发提供了有希望的候选药物。我们之前的工作包括系统的植物化学分离AM和初步的抗ad活性评估，通过这些评估，我们确定了苍术内酯A1是一种神经保护铅。为了进一步优化药效，我们通过对A1的外环进行结构修饰，合成了一小部分新的白术内酯衍生物。其中B7具有抑制自身和Cu2+诱导的Aβ聚集、保护神经元和小胶质细胞、减轻体内Aβ毒性等最广泛的活性。A1的外环酯被证明是一个可行的修饰位点，B7作为一种有前途的多靶点先导物用于阿尔茨海默病的治疗。

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引用次数: 0

Synthesis of novel 6-azacytidine prodrugs as potent influenza A inhibitors 新型6-氮杂胞苷前药强效甲型流感抑制剂的合成。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-15 DOI: 10.1016/j.bmcl.2025.130473

Omar Moukha-Chafiq , Larry D. Bratton , Shuklendu D. Karyakarte , Kathy Keith , Yohanka Martinez-Gzegozewska , Sarath C. Sarngadharan , Lynn Rasmussen , Bob Bostwick , Ashish K. Pathak , Richard Whitley , Corinne E. Augelli-Szafran

We report the synthesis and evaluation of novel prodrugs of 6-azacytidine (6-AzaCyd) to identify potent and bioavailable inhibitors of influenza A viruses. Prodrug N⁴–2-propylpentanamide 6-AzaCyd 6a was identified, through a nucleoside prodrug strategy, with a promising potency profile [H1N1-EC₉₀ = 2.6 μM, VTR = 3 at 10 μM; H3N2-EC₉₀ = 3.5 μM, VTR = 2.8 at 10 μM in MDCK cells; EC₅₀ = 2.1 μM from cap snatching polymerase U2-PB2 assay; cytotoxicity CC₅₀ > 40 μM in A549 cells; CC₅₀ > 20 μM in MDCK cells] and an acceptable absorption, distribution, metabolism and excretion (ADME) profile [mouse liver microsome (MLM) t_1/2 = 105 min, human liver microsome (HLM) t_1/2 = 65 min, Solubility = 77 μM]. Compound 6a also exhibited acceptable pharmacokinetic properties via intraperitoneal (i.p.) route of administration. The details for the synthesis of 6-AzaCyd prodrugs and anti-influenza A activity are described herein.

我们报道了新型6-氮杂胞苷（6-AzaCyd）前药的合成和评价，以鉴定有效的和生物可利用的甲型流感病毒抑制剂。前药n4 -2-丙基戊酰胺6-AzaCyd 6a通过核苷前药策略鉴定，具有良好的效价谱[H1N1-EC90 = 2.6 μM, VTR = 3 at 10 μM；MDCK细胞中H3N2-EC90 = 3.5 μM, VTR = 2.8 at 10 μM；EC50 = 2.1 μM从抓帽聚合酶2- pb2测定；细胞毒性CC50 > 40；CC50 > 20 MDCK细胞)和可接受的吸收、分布、代谢和排泄(ADME)概要(鼠肝微粒体(传销)t1/2 = 105 分钟,人类肝脏微粒体(高)t1/2 = 65 分钟,溶解度 = 77 μM]。化合物6a通过腹腔（i.p）给药途径表现出良好的药代动力学特性。本文详细介绍了6-氮杂酸苷前药的合成及其抗甲型流感活性。

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引用次数: 0

Investigation of the combinatorial anticancer effects of imidazolium-based ionic liquids and lysosomotropic detergents with cisplatin and doxorubicin 咪唑类离子液体与顺铂、阿霉素溶酶收缩剂联合抗癌效果的研究。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-15 DOI: 10.1016/j.bmcl.2025.130474

Anastasiia Gryniukova , Sergiy Rogalsky , Petro Borysko , Diana Hodyna , Vasyl Kovalishyn , Larysa Metelytsia

In the context of rapidly developing resistance caused by mutations in genes that control oncogenic pathways and cancer cell survival, as well as to known and widely accessible antitumor drugs, combined strategies are critical as a modern approach to cancer therapy. The in vitro results from a study of several long-chain N-alkylimidazole derivatives, combined with the known anticancer drugs doxorubicin and cisplatin, using cell lines of chronic myeloid leukemia K562, neuroblastoma SK-N-DZ, and mammary gland adenocarcinoma MCF7, show that the imidazolium-based ionic liquids 1-dodecyl-3-methylimidazolium chloride (IMC₁₂C₁-Cl), 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride (IMC₁CH₂COOC₁₂-Cl), and, to a lesser extent, lysosomotropic detergent 1-dodecylimidazole (IMC₁₂) consistently stand out as the most promising across all cell lines. IMC₁₂C₁-Cl demonstrated significant reductions in cisplatin and doxorubicin doses, along with enhanced cytotoxic effects, in both K562 and SK-N-DZ cells, with DRI values of 4.36 μM for cisplatin and 15.00 μM for doxorubicin. IMC₁CH₂COOC₁₂-Cl showed high DRI and synergism in MCF7 cells and moderate activity in SK-N-DZ cells. IMC₁₂C₁-Cl and IMC₁CH₂COOC₁₂-Cl appear to be promising candidates for the development and evaluation of their combinatorial anticancer effects.

在控制致癌途径和癌细胞存活的基因突变引起的耐药性迅速发展的背景下，以及已知和广泛可获得的抗肿瘤药物，联合策略作为癌症治疗的现代方法至关重要。用慢性髓性白血病K562、神经母细胞瘤SK-N-DZ和乳腺腺癌MCF7细胞系对几种长链n -烷基咪唑衍生物与已知抗癌药物多柔比星和顺platin联合进行的体外实验结果表明，咪唑基离子液体1-十二烷基-3-甲基咪唑氯（IMC12C1-Cl）、1-十二烷基氧羰基甲基-3-甲基咪唑氯（IMC1CH2COOC12-Cl），以及在较小程度上溶酶促体清洁剂1-十二烷基咪唑（IMC12）在所有细胞系中一直是最有前途的。在K562和SK-N-DZ细胞中，IMC12C1-Cl显示出顺铂和阿霉素剂量的显著降低，以及细胞毒性作用的增强，顺铂和阿霉素的DRI值分别为4.36 μM和15.00 μM。IMC1CH2COOC12-Cl在MCF7细胞中表现出高DRI和协同作用，在SK-N-DZ细胞中表现出中等活性。IMC12C1-Cl和IMC1CH2COOC12-Cl似乎是开发和评估其联合抗癌作用的有希望的候选者。

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引用次数: 0

Synthesis of dehydroabietic acid derivatives as mast cell stabilizers 作为肥大细胞稳定剂的脱氢枞酸衍生物的合成。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-14 DOI: 10.1016/j.bmcl.2025.130477

Tao Zeng , Wenchao Yu , Chenming Gu , Jian-Guo Fu , Motahareh Asgari , Yiming Li , Fei Qian , Chen-Guo Feng

Mast cell degranulation plays a central role in IgE-driven allergic diseases, yet the therapeutic options for stabilizers remain limited. Rosinane diterpenoids, a class of natural polyphenols known for their anti-inflammatory properties, represent an attractive source for novel anti-allergic compounds. Dehydroabietic acid (DHAA), a member of this class, exhibits diverse biological activities, yet its potential in mast cell regulation remains unexplored. In this study, we designed and synthesized a series of novel DHAA derivatives. We evaluated their anti-allergic effects in IgE/antigen-stimulated bone marrow-derived mast cells (BMMCs), and found that compound 4f significantly and dose-dependently inhibited IgE-mediated Ca²⁺ influx and suppressed mast cell degranulation. Moreover, in vivo studies demonstrated that compound 4f effectively attenuated passive cutaneous anaphylaxis in mice and reduced vascular leakage. These findings indicate that compound 4f represents a novel mast cell stabilizer and provides a promising structural scaffold for developing new anti-allergic therapeutics.

肥大细胞脱颗粒在ige驱动的过敏性疾病中起核心作用，但稳定剂的治疗选择仍然有限。松香烷二萜是一类天然多酚，以其抗炎特性而闻名，是新型抗过敏化合物的一个有吸引力的来源。脱氢枞酸（DHAA）是这类化合物中的一员，具有多种生物活性，但其在肥大细胞调节中的潜力尚未被发掘。在这项研究中，我们设计并合成了一系列新的DHAA衍生物。我们评估了它们在IgE/抗原刺激的骨髓源性肥大细胞（BMMCs）中的抗过敏作用，发现化合物4f显著且剂量依赖性地抑制IgE介导的Ca2+内流并抑制肥大细胞脱颗粒。此外，体内研究表明，化合物4f能有效减轻小鼠被动皮肤过敏反应，减少血管渗漏。这些发现表明，化合物4f代表了一种新的肥大细胞稳定剂，为开发新的抗过敏疗法提供了一个有希望的结构支架。

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引用次数: 0

Structure-based discovery of sulfamoyl-ethyl-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine amides and sulfonamides as potent B-Cell Lymphoma 6 (BCL6)-BTB inhibitors 基于结构的磺胺酰基-乙基-4-氧-3,4-二氢- 7h -吡咯[2,3-d]嘧啶酰胺和磺胺类药物作为b细胞淋巴瘤6 (BCL6)-BTB抑制剂的发现

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-13 DOI: 10.1016/j.bmcl.2025.130471

Ahmed Mamai , Mohammed M. Morshed , Michael Prakesch , Gennady Poda , Pandiaraju Subramanian , Anh M. Chau , Iain D.G. Watson , Babu Joseph , Brian Wilson , Justin A. Morin , Richard Marcellus , Brigitte Theriault , Mohammed Mohammed , Ayome Abibi , Manuel Chan , Taira Kiyota , Ahmed Aman , Ratheesh Subramaniam , Craig Strathdee , Jeffrey Winston , Rima Al-awar

Diffuse Large B-Cell Lymphoma (DLBCL) is one of the most aggressive forms of lymphoid malignancies. About 40 % of patients eventually relapse and succumb to the disease within 5 years after diagnosis, underscoring the need for new treatment modalities. B-Cell Lymphoma 6 protein (BCL6) is a repressive transcription factor that is dysregulated in about 40 % of DLBCLs. As a rationale for pursuing BCL6 as a drug target, disrupting complexes between this protein and its co-repressors is thought to mitigate the downstream oncogenic effects of this pathway. However, drugging transcription factors presents a formidable undertaking since targeting protein–protein interactions has historically been challenging. In this study, we used X-ray structures of BCL6-SMRT (a silencing mediator for retinoid or thyroid-hormone receptors, also known as the nuclear receptor co-repressor 2, NCOR2) peptide and compound 79-6 to conduct a virtual screen of a library of 5.2 million compounds. Through this exercise, we identified the pyrrolopyridone 3 as a viable hit, which in turn led to the identification of pyrrolopyrimidone lead compound 4. The X-ray crystal structure of 4 bound to the BTB (Broad-Complex, Tramtrack, and Bric à brac) domain of BCL6 revealed a large back pocket as well as a left-hand channel adjacent to the ligand that could be leveraged to optimize these compounds. Sulfonamide side chains were therefore introduced to target this space, leading to compounds 11d and 11e having sub-micromolar binding to the BTB domain of BCL6.

弥漫性大b细胞淋巴瘤（DLBCL）是最具侵袭性的淋巴细胞恶性肿瘤之一。约40% %的患者最终复发，并在确诊后5 年内死于疾病，强调需要新的治疗方式。b细胞淋巴瘤6蛋白（BCL6）是一种抑制转录因子，在约40% %的dlbcl中失调。作为追求BCL6作为药物靶点的基本原理，破坏该蛋白及其协同抑制物之间的复合物被认为可以减轻该途径的下游致癌作用。然而，药物转录因子呈现出一项艰巨的任务，因为靶向蛋白质-蛋白质相互作用历来具有挑战性。在这项研究中，我们利用BCL6-SMRT（类视黄醇或甲状腺激素受体的沉默介质，也称为核受体协同抑制因子2，NCOR2）肽和化合物79-6的x射线结构对520万种化合物进行了虚拟筛选。通过这项工作，我们确定了吡咯吡啶酮3是可行的打击，这反过来又导致了吡咯吡啶酮先导化合物4的鉴定。结合BCL6的BTB （Broad-Complex， Tramtrack和Bric - brac）结构域的x射线晶体结构显示了一个大的后口袋以及一个与配体相邻的左手通道，可以用来优化这些化合物。因此，磺胺侧链被引入到这个空间，导致化合物11d和11e与BCL6的BTB结构域具有亚微摩尔结合。

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引用次数: 0

Precision engineering of adalimumab fab variants enhances TNF-α neutralization and structural stability 阿达木单抗fab变体的精密工程增强了TNF-α中和和结构稳定性。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-13 DOI: 10.1016/j.bmcl.2025.130475

Abida Khan , Abdullah R. Alzahrani , Zia Ur Rehman , Syeda Huma H. Zaidi , Abdul Hai , Maha M. Al-Bazi , Abeer A. Banjabi , Mohd Imran

The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) plays a substantial role in the advancement of various autoimmune diseases and is mostly suppressed by the monoclonal antibody adalimumab (Humira). This study utilized a rational in-silico method to design and optimize adalimumab Fab mutants with enhanced TNF-α binding affinity. A total of 512 mutants were produced with a Python automation script and FoldX. Eight mutants were selected for further analysed based on their stability (ΔG). The humanness ratings of the chosen variations were computed, demonstrating that they preserved similar human-like attributes. The anticipated expression in E. coli was elevated, with values between 0.93 and 0.94, as evidenced by the solubility analysis, which was analogous to the control (adalimumab) result of 0.94. Molecular docking revealed that all mutants displayed negligible RMSD values (≤ 0.001 Å) and uniform interface residues. FreeSASA and MM/GBSA studies were conducted to identify the top three candidates (Antibody-98, Antibody-354, and Antibody-374), which were subsequently confirmed by molecular dynamics simulations. Antibody-374 (yellow) and Antibody-98 (green) exhibit negligible variations (∼0.2–0.3 nm). Relative to the control, all three mutants demonstrated an elevation in total buried surface area (BSA), with Antibody-354 displaying the greatest measurement (5434.06 Å²). Antibody-98 exhibited 14–15 hydrogen bonds, which were sustained at about 8–10 bonds for the majority of the simulation. Antibody-354 exhibited a range of 6–8 number of hydrogen bonds, while Antibody-374 had a robust contact with 6–10 hydrogen bonds. In the binding free energy examination utilizing MM/GBSA, Antibody-374 exhibited the most advantageous ΔG_total (−36.67 kcal/mol), succeeded by Antibody-98 (−30.07 kcal/mol) and Antibody-354 (−25.47 kcal/mol). These antibodies surpassed the wild-type docked model (−24.80 kcal/mol) and the native crystal complex (−25.46 kcal/mol). The enhancements were ascribed to particular point mutations, namely G28S, R90E, Y96W (light chain), and W53Y/F, L102I/V (heavy chain), which augmented molecular interactions and complex stability. This study demonstrated the capability of computational antibody engineering to generate Fab variants with enhanced binding affinity and stability for TNF-α. These findings thus offer significant insights for the advancement of future biologic therapies.

促炎细胞因子肿瘤坏死因子-α (TNF-α)在各种自身免疫性疾病的进展中起重要作用，主要被单克隆抗体阿达木单抗（Humira）抑制。本研究利用合理的芯片方法设计和优化阿达木单抗Fab突变体，增强TNF-α结合亲和力。使用Python自动化脚本和FoldX总共产生了512个突变体。根据其稳定性选择了8个突变体进行进一步分析（ΔG）。计算了所选变异的人类等级，证明它们保留了类似人类的属性。在大肠杆菌中的预期表达量升高，其值在0.93和0.94之间，这与对照组（阿达木单抗）的0.94结果相似。分子对接显示，所有突变体的RMSD值均可忽略不计（≤0.001 Å），界面残基均匀。通过FreeSASA和MM/GBSA研究确定了前三名候选药物（Antibody-98、Antibody-354和Antibody-374），随后通过分子动力学模拟证实。抗体-374（黄色）和抗体-98（绿色）的变化可以忽略不计（~0.2-0.3 nm）。与对照相比，所有三种突变体的总掩埋表面积（BSA）均有所升高，其中抗体354的测量值最大（5434.06 Å2）。抗体-98具有14-15个氢键，在模拟的大部分时间里，这些氢键维持在8-10个左右。抗体-354具有6-8个氢键，而抗体-374具有6-10个氢键。在结合自由能检测中，抗体374表现出最大优势ΔGtotal(-36.67 kcal/mol)，其次是抗体98（-30.07 kcal/mol）和抗体354（-25.47 kcal/mol）。这些抗体超过了野生型对接模型（-24.80 kcal/mol）和天然晶体配合物（-25.46 kcal/mol）。这种增强归因于特定的点突变，即G28S、R90E、Y96W（轻链）和W53Y/F、L102I/V（重链），它们增强了分子相互作用和复合物的稳定性。本研究证明了计算抗体工程能够产生对TNF-α具有增强结合亲和力和稳定性的Fab变体。因此，这些发现为未来生物疗法的发展提供了重要的见解。

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