Medicine in Drug Discovery最新文献

Enhancing the therapeutic potential of plumbagin in breast cancer via advanced nanomedicine approaches 通过先进的纳米医学方法增强白桦素在乳腺癌中的治疗潜力

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2026-02-01 DOI: 10.1016/j.medidd.2026.100250

K.Trideva Sastri , N.P. Gana , Nischal Chandra , Rupshee Jain , Vikas Jain

Plumbagin, a bioactive naphthoquinone from Plumbago species, has emerged as a pleiotropic anticancer candidate with activity across major breast cancer subtypes. Preclinical evidence indicates that plumbagin suppresses tumour growth by converging on redox stress and survival circuitry, including mitochondrial apoptosis and NF-κB-linked pathways, with reported inhibitory effects in ER-positive, HER2-overexpressing, and triple-negative models and a signal of relative selectivity in normal breast cells. Beyond cytotoxicity, plumbagin can attenuate metastatic programs, notably by NF-κB-dependent repression of CXCR4, thereby reducing migration and invasion. However, its clinical plausibility is constrained by poor solubility, exposure instability, and a narrow therapeutic window driven by quinone-mediated off-target oxidative burden. Advanced nanocarriers offer a rational strategy to convert this redox liability into tumour-selective benefit through exposure shaping, stimulus-responsive release, and conservative, clinically familiar excipient choices. Emerging designs—including long-circulating systems, ROS/GSH-activated approaches, and antioxidant interface engineering—aim to flatten peak-related toxicity while sustaining intratumoural pharmacodynamic thresholds. Co-delivery platforms may further synchronize pharmacology to overcome resistance, pairing plumbagin with cytotoxins or pathway modulators through programmable release sequencing. Looking ahead, AI/ML-guided formulation and imaging-integrated theranostics can support biomarker-driven dose selection and a pragmatic Phase I roadmap that adheres to transparent CMC principles. Collectively, these advances position plumbagin-based nanomedicine as a credible, mechanism-informed phytotherapeutic strategy for breast cancers with high unmet need, warranting carefully designed translational studies.

Plumbagin是一种从plumbagago属植物中提取的具有生物活性的萘醌，已成为一种多效性的抗癌候选药物，在主要的乳腺癌亚型中具有活性。临床前证据表明，白丹素通过聚合氧化还原应激和生存通路（包括线粒体凋亡和NF-κ b相关通路）抑制肿瘤生长，在er阳性、her2过表达和三阴性模型中具有抑制作用，在正常乳腺细胞中具有相对选择性。除了细胞毒性外，白桦素还可以减弱转移程序，特别是通过NF-κ b依赖性抑制CXCR4，从而减少迁移和侵袭。然而，其临床可行性受到溶解度差、暴露不稳定以及醌介导的脱靶氧化负担驱动的狭窄治疗窗口的限制。先进的纳米载体提供了一种合理的策略，通过暴露形成、刺激反应释放和保守的、临床熟悉的赋形剂选择，将这种氧化还原倾向转化为肿瘤选择性益处。新兴设计——包括长循环系统、ROS/ gsh激活方法和抗氧化界面工程——旨在降低峰值相关毒性，同时维持肿瘤内药效学阈值。通过可编程释放测序，将白桦白素与细胞毒素或途径调节剂配对，共同递送平台可能进一步同步药理学以克服耐药性。展望未来，人工智能/机器学习指导的配方和成像集成治疗可以支持生物标志物驱动的剂量选择和坚持透明CMC原则的实用I期路线图。总的来说，这些进展将基于白桦素的纳米药物定位为一种可靠的、机制知情的植物治疗策略，用于高度未满足需求的乳腺癌，需要精心设计的转化研究。

{"title":"Enhancing the therapeutic potential of plumbagin in breast cancer via advanced nanomedicine approaches","authors":"K.Trideva Sastri , N.P. Gana , Nischal Chandra , Rupshee Jain , Vikas Jain","doi":"10.1016/j.medidd.2026.100250","DOIUrl":"10.1016/j.medidd.2026.100250","url":null,"abstract":"<div><div>Plumbagin, a bioactive naphthoquinone from Plumbago species, has emerged as a pleiotropic anticancer candidate with activity across major breast cancer subtypes. Preclinical evidence indicates that plumbagin suppresses tumour growth by converging on redox stress and survival circuitry, including mitochondrial apoptosis and NF-κB-linked pathways, with reported inhibitory effects in ER-positive, HER2-overexpressing, and triple-negative models and a signal of relative selectivity in normal breast cells. Beyond cytotoxicity, plumbagin can attenuate metastatic programs, notably by NF-κB-dependent repression of CXCR4, thereby reducing migration and invasion. However, its clinical plausibility is constrained by poor solubility, exposure instability, and a narrow therapeutic window driven by quinone-mediated off-target oxidative burden. Advanced nanocarriers offer a rational strategy to convert this redox liability into tumour-selective benefit through exposure shaping, stimulus-responsive release, and conservative, clinically familiar excipient choices. Emerging designs—including long-circulating systems, ROS/GSH-activated approaches, and antioxidant interface engineering—aim to flatten peak-related toxicity while sustaining intratumoural pharmacodynamic thresholds. Co-delivery platforms may further synchronize pharmacology to overcome resistance, pairing plumbagin with cytotoxins or pathway modulators through programmable release sequencing. Looking ahead, AI/ML-guided formulation and imaging-integrated theranostics can support biomarker-driven dose selection and a pragmatic Phase I roadmap that adheres to transparent CMC principles. Collectively, these advances position plumbagin-based nanomedicine as a credible, mechanism-informed phytotherapeutic strategy for breast cancers with high unmet need, warranting carefully designed translational studies.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100250"},"PeriodicalIF":0.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Energy-based method for designing aptamers to target phosphatidylcholine 磷脂酰胆碱适配体的能量设计方法

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2026-01-22 DOI: 10.1016/j.medidd.2026.100247

Fatima Alharbi , Hamed Alsulami , Suliman AlOmar , Md. Ashrafuzzaman

Diverse technologies are used to design nucleic acid aptamers to achieve targeted therapeutics, engineer diagnostic tools to detect specific biomolecules associated with disease-oriented signaling pathways, and develop drug delivery systems. Despite the availability of many methods, including systematic evolution of ligands by exponential enrichment, there is no reliable method that can address aptamer-target binding energetics during aptamer design. We have developed a technique to do so, combining theoretical and computational methods. In this energy-based method, we calculate drug-target binding energies (DTBEs) and monitor phenomenological drug-target binding energetics related to drug-target association/dissociation processes, considering screened Coulomb interactions (SCIs) among a distribution of functional charges in a complex of an aptamer or aptamer building block (ABB) and target biomolecule in the biological environment where interactions take place. An ABB is any nucleotide: adenine, guanine, cytosine, uracil (for RNA), or thymine (for DNA). We have designed a set of novel aptamers for phosphatidylcholine, an important biomolecule relevant to various therapeutics, that are outlined here. In summary, our drug designing method involves constructing an aptamer using a seed-and-grow approach, optimizing SCIs, and selecting aptamer length based on the trend of DTBE in an aqueous environment, where aptamers interact with target(s). This novel technique, the screened Coulomb interaction approach (SCIA), ensures the discovery of target-specific aptamers as the target specificity is inherently incorporated during the aptamer design phases. SCIA is expected to significantly enhance aptamer discovery research and help develop aptamer-based therapeutics for diseases where specific drug targets are known.

多种技术被用于设计核酸适体以实现靶向治疗，设计诊断工具以检测与疾病导向信号通路相关的特定生物分子，以及开发药物递送系统。尽管有许多方法可用，包括通过指数富集的配体系统进化，但在适体设计过程中，没有可靠的方法可以解决适体-靶结合能量的问题。我们已经开发了一种技术来做到这一点，结合理论和计算方法。在这种基于能量的方法中，我们计算药物-靶标结合能（DTBEs）并监测与药物-靶标结合/解离过程相关的现象学药物-靶标结合能，考虑筛选的库仑相互作用（SCIs），在生物环境中，适体或适体构建块（ABB）和目标生物分子的复合物中的功能电荷分布之间发生相互作用。ABB是任何核苷酸：腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶（RNA）或胸腺嘧啶（DNA）。我们设计了一套新的磷脂酰胆碱适配体，这是一种与各种治疗相关的重要生物分子，在这里概述。总之，我们的药物设计方法包括使用种子-生长方法构建适体，优化SCIs，并根据适体与靶标相互作用的水环境中DTBE的趋势选择适体长度。这种新技术，筛选库仑相互作用方法（SCIA），确保发现目标特异性适配体，因为目标特异性在适配体设计阶段固有地包含。SCIA有望显著加强适体发现研究，并帮助开发基于适体的治疗方法，用于已知特定药物靶点的疾病。

{"title":"Energy-based method for designing aptamers to target phosphatidylcholine","authors":"Fatima Alharbi , Hamed Alsulami , Suliman AlOmar , Md. Ashrafuzzaman","doi":"10.1016/j.medidd.2026.100247","DOIUrl":"10.1016/j.medidd.2026.100247","url":null,"abstract":"<div><div>Diverse technologies are used to design nucleic acid aptamers to achieve targeted therapeutics, engineer diagnostic tools to detect specific biomolecules associated with disease-oriented signaling pathways, and develop drug delivery systems. Despite the availability of many methods, including systematic evolution of ligands by exponential enrichment, there is no reliable method that can address aptamer-target binding energetics during aptamer design. We have developed a technique to do so, combining theoretical and computational methods. In this energy-based method, we calculate drug-target binding energies (DTBEs) and monitor phenomenological drug-target binding energetics related to drug-target association/dissociation processes, considering screened Coulomb interactions (SCIs) among a distribution of functional charges in a complex of an aptamer or aptamer building block (ABB) and target biomolecule in the biological environment where interactions take place. An ABB is any nucleotide: adenine, guanine, cytosine, uracil (for RNA), or thymine (for DNA). We have designed a set of novel aptamers for phosphatidylcholine, an important biomolecule relevant to various therapeutics, that are outlined here. In summary, our drug designing method involves constructing an aptamer using a seed-and-grow approach, optimizing SCIs, and selecting aptamer length based on the trend of DTBE in an aqueous environment, where aptamers interact with target(s). This novel technique, the screened Coulomb interaction approach (SCIA), ensures the discovery of target-specific aptamers as the target specificity is inherently incorporated during the aptamer design phases. SCIA is expected to significantly enhance aptamer discovery research and help develop aptamer-based therapeutics for diseases where specific drug targets are known.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100247"},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From ferments to fixers: Postbiotics in wound healing 从发酵剂到固定剂：后生物制剂在伤口愈合中的应用

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2026-01-12 DOI: 10.1016/j.medidd.2026.100249

Hui Sin Lim , Christopher J. Serpell , Satoshi Ogawa , Yong Yu Hu , Eng Hwa Wong

The skin acts as a vital barrier against the environment, and injuries can lead to acute or chronic wounds. Chronic wounds often heal slowly and are more susceptible to infection. Postbiotics, defined as preparations of inactivated microorganisms or their bioactive components, have demonstrated potential to promote wound repair. Compared with live probiotics, postbiotics are safer, more stable, and easier to standardise, while still supporting tissue repair via antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects. Compounds such as exopolysaccharides, short-chain fatty acids, antimicrobial peptides, enzymes, vitamins, and cell-free supernatants can enhance fibroblast growth, collagen production, keratinocyte migration, angiogenesis, and immune balance. Postbiotics derived from Lactobacillus, Bifidobacterium, Bacillus, and commensal Staphylococcus species act through multiple signalling pathways. They reduce pro-inflammatory cytokines, promote alternatively activated M2 macrophage polarisation, and facilitate restoration of the skin barrier. Recent developments in hydrogels, nanofibers, and encapsulated delivery systems have improved the stability and availability of postbiotic compounds at wound sites, making them more effective. Despite promising results from preclinical studies and early clinical trials, challenges remain in standardizing production, defining regulatory frameworks, and generating strong clinical evidence. Future studies should focus on identifying key bioactive molecules using advanced omics approaches, developing targeted delivery systems, and evaluating postbiotic therapies in well-designed clinical trials. Overall, postbiotics provide a safe and versatile approach to accelerate wound healing and may serve as an alternative or complement to conventional treatments.

皮肤是抵御环境的重要屏障，受伤可导致急性或慢性伤口。慢性伤口往往愈合缓慢，更容易感染。后生物制剂，定义为灭活微生物或其生物活性成分的制剂，已被证明具有促进伤口修复的潜力。与活的益生菌相比，后益生菌更安全、更稳定、更容易标准化，同时仍然通过抗菌、抗炎、抗氧化和免疫调节作用支持组织修复。外多糖、短链脂肪酸、抗菌肽、酶、维生素和无细胞上清液等化合物可以促进成纤维细胞生长、胶原蛋白生成、角质细胞迁移、血管生成和免疫平衡。来自乳杆菌、双歧杆菌、芽孢杆菌和共生葡萄球菌的后生菌通过多种信号通路起作用。它们减少促炎细胞因子，促进交替激活的M2巨噬细胞极化，促进皮肤屏障的修复。水凝胶、纳米纤维和封装递送系统的最新发展提高了生物后化合物在伤口部位的稳定性和可用性，使其更有效。尽管临床前研究和早期临床试验取得了可喜的结果，但在标准化生产、确定监管框架和产生强有力的临床证据方面仍然存在挑战。未来的研究应集中于利用先进的组学方法识别关键的生物活性分子，开发靶向给药系统，并在精心设计的临床试验中评估生物后疗法。总的来说，后生物制剂提供了一种安全和通用的方法来加速伤口愈合，可以作为传统治疗的替代或补充。

{"title":"From ferments to fixers: Postbiotics in wound healing","authors":"Hui Sin Lim , Christopher J. Serpell , Satoshi Ogawa , Yong Yu Hu , Eng Hwa Wong","doi":"10.1016/j.medidd.2026.100249","DOIUrl":"10.1016/j.medidd.2026.100249","url":null,"abstract":"<div><div>The skin acts as a vital barrier against the environment, and injuries can lead to acute or chronic wounds. Chronic wounds often heal slowly and are more susceptible to infection. Postbiotics, defined as preparations of inactivated microorganisms or their bioactive components, have demonstrated potential to promote wound repair. Compared with live probiotics, postbiotics are safer, more stable, and easier to standardise, while still supporting tissue repair via antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects. Compounds such as exopolysaccharides, short-chain fatty acids, antimicrobial peptides, enzymes, vitamins, and cell-free supernatants can enhance fibroblast growth, collagen production, keratinocyte migration, angiogenesis, and immune balance. Postbiotics derived from <em>Lactobacillus</em>, <em>Bifidobacterium</em>, <em>Bacillus</em>, and commensal <em>Staphylococcus</em> species act through multiple signalling pathways. They reduce pro-inflammatory cytokines, promote alternatively activated M2 macrophage polarisation, and facilitate restoration of the skin barrier. Recent developments in hydrogels, nanofibers, and encapsulated delivery systems have improved the stability and availability of postbiotic compounds at wound sites, making them more effective. Despite promising results from preclinical studies and early clinical trials, challenges remain in standardizing production, defining regulatory frameworks, and generating strong clinical evidence. Future studies should focus on identifying key bioactive molecules using advanced omics approaches, developing targeted delivery systems, and evaluating postbiotic therapies in well-designed clinical trials. Overall, postbiotics provide a safe and versatile approach to accelerate wound healing and may serve as an alternative or complement to conventional treatments.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100249"},"PeriodicalIF":0.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intravenous and oral NOAEL doses of the new PrC-210 aminothiol in swine and dose equivalency in humans to enable clinical trials 新型PrC-210氨基硫醇在猪体内静脉注射和口服NOAEL剂量以及在人体内的剂量等效性，以便进行临床试验

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2026-01-12 DOI: 10.1016/j.medidd.2026.100248

William E. Fahl , Bryan L. Fahl , Aaron M. Dingle

Reactive Oxygen Species (ROS)-induced cell and organ toxicity is a common element in human disease patho-mechanisms. PrC-210 is a new free-radical scavenger that substantially suppresses ROS damage in pre-clinical animal disease models. Here we determined PrC-210 pharmacokinetic and toxicokinetic performance in a large animal pig model as a forestep to Phase 1 safety studies in humans. Using a newly created LC-MS assay to measure plasma PrC-210 levels, we determined that: i) an IV or oral PrC-210 bolus dose yielded easily measurable plasma concentrations, which returned to baseline within an hour (IV) or 8–10 h (oral), ii) at the same IV mg/kg dose, female pig plasma PrC-210 AUC levels were 13–15 % higher than males; this presumably reflects less vasculature per unit tissue mass, iii) a primary toxicity, vomiting, followed simple PrC-210 plasma toxicokinetics for both IV and oral doses, and was absent at IV PrC-210 NOAEL (5.0 mg/kg bw) and oral PrC-210 NOAEL (70.0 mg/kg bw) doses that are at least two-fold higher than the highest PrC-210 dose that would be administered therapeutically, iv) no significant changes in blood cell populations were seen through 7 days following an IV PrC-210 bolus NOAEL dose, v) no significant changes in any of 15 blood chemistry parameters were seen through 7 days following an IV PrC-210 NOAEL dose, and vi) no discernible visible nor histologic organ or tissue pathology was seen in necropsies performed at 7 days post-IV dose. This study supports continued development of PrC-210 for Phase 1 human studies.

活性氧（ROS）诱导的细胞和器官毒性是人类疾病病理机制中的一个共同因素。PrC-210是一种新的自由基清除剂，在临床前动物疾病模型中显著抑制ROS损伤。在此，我们在大型动物猪模型中测定了PrC-210的药代动力学和毒代动力学性能，作为人类1期安全性研究的前驱。使用新创建的LC-MS测定血浆PrC-210水平，我们确定：i)静脉注射或口服PrC-210丸剂产生易于测量的血浆浓度，在1小时（IV）或8-10小时（口服）内恢复到基线水平；ii)在相同的静脉注射mg/kg剂量下，母猪血浆PrC-210 AUC水平比雄性高13 - 15%；这大概反映了单位组织质量,更少的脉管系统iii)主要毒性、呕吐、遵循简单prc - 210等离子体毒性动力学IV和口服剂量,和没有第四prc - 210,科学(5.0毫克/公斤体重),口服prc - 210,科学(70.0毫克/公斤体重)至少两方面高于最高剂量prc - 210剂量治疗管理,(四)血细胞数量无显著变化被认为通过7天之后第四prc - 210丸,科学剂量,v)在静脉注射PrC-210 NOAEL后7天内，15项血液化学参数均未见显著变化，vi)在静脉注射后7天进行的尸检中未见明显可见或组织学上的器官或组织病理。本研究支持继续开发PrC-210用于1期人体研究。

{"title":"Intravenous and oral NOAEL doses of the new PrC-210 aminothiol in swine and dose equivalency in humans to enable clinical trials","authors":"William E. Fahl , Bryan L. Fahl , Aaron M. Dingle","doi":"10.1016/j.medidd.2026.100248","DOIUrl":"10.1016/j.medidd.2026.100248","url":null,"abstract":"<div><div>Reactive Oxygen Species (ROS)-induced cell and organ toxicity is a common element in human disease patho-mechanisms. PrC-210 is a new free-radical scavenger that substantially suppresses ROS damage in pre-clinical animal disease models. Here we determined PrC-210 pharmacokinetic and toxicokinetic performance in a large animal pig model as a forestep to Phase 1 safety studies in humans. Using a newly created LC-MS assay to measure plasma PrC-210 levels, we determined that: i) an IV or oral PrC-210 bolus dose yielded easily measurable plasma concentrations, which returned to baseline within an hour (IV) or 8–10 h (oral), ii) at the same IV mg/kg dose, female pig plasma PrC-210 AUC levels were 13–15 % higher than males; this presumably reflects less vasculature per unit tissue mass, iii) a primary toxicity, vomiting, followed simple PrC-210 plasma toxicokinetics for both IV and oral doses, and was absent at IV PrC-210 NOAEL (5.0 mg/kg bw) and oral PrC-210 NOAEL (70.0 mg/kg bw) doses that are at least two-fold higher than the highest PrC-210 dose that would be administered therapeutically, iv) no significant changes in blood cell populations were seen through 7 days following an IV PrC-210 bolus NOAEL dose, v) no significant changes in any of 15 blood chemistry parameters were seen through 7 days following an IV PrC-210 NOAEL dose, and vi) no discernible visible nor histologic organ or tissue pathology was seen in necropsies performed at 7 days post-IV dose. This study supports continued development of PrC-210 for Phase 1 human studies.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100248"},"PeriodicalIF":0.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Microbiota-derived metabolites in cancer: Dual roles in pathogenesis and opportunities for therapy 癌症中微生物衍生代谢物：在发病机制和治疗机会中的双重作用

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-30 DOI: 10.1016/j.medidd.2025.100245

Muskan Rajak , Debabrata Dash , Raj Kumar Koiri

The gut microbiota has emerged as a determinant of onset, progression, and response to treatment of many cancers. The current research in oncology indicates that microbial metabolites like short-chain fatty acids (SCFAs), secondary bile acids, indole derivatives, and polyamines are not passive metabolic end products but potent bioactive mediators. These molecules directly modulate cellular signaling pathways, immune modulation, and the tumor microenvironment. Depending on their concentration and the overall physiological environment, these metabolites may be tumorigenic or protective, anticancer in effect. Significantly, by controlling immune reactions and drug metabolism, microbiota-derived metabolites have been reported to modulate and enhance the activity of chemotherapeutic agents, radiotherapy, and immunotherapeutic protocols.

In spite of these advances, it is still difficult to apply microbiome research to clinical oncology. Some of the key hurdles are high interindividual heterogeneity in gut microbial structure, lack of standardized analysis pipelines, and incomplete understanding of mechanistic crosstalk between the host and microbiome. This heterogeneity makes reproducibility tricky and reduces the predictive value of microbiota-directed interventions in oncology. However, emerging advances in metabolomics, synthetic biology, and systems-level medicine are enabling personalized therapy discovery. Such technological advances facilitate massive profiling and individually customized modulation of microbial metabolites, thus promoting the development of metabolite-directed or microbiota-targeted adjuvant strategies that promise augmented specificity and therapeutic efficacy.

This review integrates existing knowledge, translational hurdles, and new trends in the translation of microbiome-derived metabolites towards precision cancer treatment. As the evidence increasingly places the gut microbiota at the interface of controlling and predicting tumor behavior and outcomes of therapy, it is a promising system for therapeutic and biomarker development. Translating these microbial metabolites by combining biotechnological and computational approaches can usher in a new era for precision oncology that is reconcilable with host–microbiome physiologies.

肠道菌群已成为许多癌症发病、进展和治疗反应的决定因素。目前肿瘤学研究表明，短链脂肪酸（SCFAs）、次级胆汁酸、吲哚衍生物和多胺等微生物代谢产物不是被动的代谢终产物，而是有效的生物活性介质。这些分子直接调节细胞信号通路、免疫调节和肿瘤微环境。根据其浓度和整体生理环境的不同，这些代谢物可能是致瘤性的，也可能是保护性的、抗癌的。值得注意的是，通过控制免疫反应和药物代谢，微生物衍生的代谢物已经被报道可以调节和增强化疗药物、放疗和免疫治疗方案的活性。尽管取得了这些进展，但将微生物组研究应用于临床肿瘤学仍然很困难。一些关键的障碍是肠道微生物结构的高度个体间异质性，缺乏标准化的分析管道，以及对宿主和微生物组之间机制串扰的不完全理解。这种异质性使得可重复性变得棘手，并降低了微生物群导向的肿瘤学干预的预测价值。然而，代谢组学、合成生物学和系统级医学的新兴进展正在使个性化治疗的发现成为可能。这些技术进步促进了微生物代谢物的大规模分析和个性化定制调节，从而促进了代谢物导向或微生物群靶向的佐剂策略的发展，这些策略有望增强特异性和治疗效果。这篇综述整合了现有的知识，翻译障碍，以及微生物衍生代谢物向精确癌症治疗的翻译的新趋势。随着越来越多的证据表明肠道微生物群在控制和预测肿瘤行为和治疗结果的界面上，它是一个很有前途的治疗和生物标志物开发系统。通过结合生物技术和计算方法来翻译这些微生物代谢物，可以开创一个与宿主-微生物组生理学相协调的精确肿瘤学的新时代。

{"title":"Microbiota-derived metabolites in cancer: Dual roles in pathogenesis and opportunities for therapy","authors":"Muskan Rajak , Debabrata Dash , Raj Kumar Koiri","doi":"10.1016/j.medidd.2025.100245","DOIUrl":"10.1016/j.medidd.2025.100245","url":null,"abstract":"<div><div>The gut microbiota has emerged as a determinant of onset, progression, and response to treatment of many cancers. The current research in oncology indicates that microbial metabolites like short-chain fatty acids (SCFAs), secondary bile acids, indole derivatives, and polyamines are not passive metabolic end products but potent bioactive mediators. These molecules directly modulate cellular signaling pathways, immune modulation, and the tumor microenvironment. Depending on their concentration and the overall physiological environment, these metabolites may be tumorigenic or protective, anticancer in effect. Significantly, by controlling immune reactions and drug metabolism, microbiota-derived metabolites have been reported to modulate and enhance the activity of chemotherapeutic agents, radiotherapy, and immunotherapeutic protocols.</div><div>In spite of these advances, it is still difficult to apply microbiome research to clinical oncology. Some of the key hurdles are high interindividual heterogeneity in gut microbial structure, lack of standardized analysis pipelines, and incomplete understanding of mechanistic crosstalk between the host and microbiome. This heterogeneity makes reproducibility tricky and reduces the predictive value of microbiota-directed interventions in oncology. However, emerging advances in metabolomics, synthetic biology, and systems-level medicine are enabling personalized therapy discovery. Such technological advances facilitate massive profiling and individually customized modulation of microbial metabolites, thus promoting the development of metabolite-directed or microbiota-targeted adjuvant strategies that promise augmented specificity and therapeutic efficacy.</div><div>This review integrates existing knowledge, translational hurdles, and new trends in the translation of microbiome-derived metabolites towards precision cancer treatment. As the evidence increasingly places the gut microbiota at the interface of controlling and predicting tumor behavior and outcomes of therapy, it is a promising system for therapeutic and biomarker development. Translating these microbial metabolites by combining biotechnological and computational approaches can usher in a new era for precision oncology that is reconcilable with host–microbiome physiologies.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100245"},"PeriodicalIF":0.0,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antiphotoaging and anti-inflammatory effects of Malaysian brown seaweed Sargassum aquifolium: Cellular insights from HaCaT and RAW 264.7 models and metabolite profiling via LC-MS 马来西亚褐藻的抗光老化和抗炎作用：HaCaT和RAW 264.7模型的细胞见解以及LC-MS代谢物分析

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-30 DOI: 10.1016/j.medidd.2025.100246

Krishnapriya Thiyagarasaiyar , Kai Xuan Lim , Chi Chen Wong , Jing Yu Lim , Bey-Hing Goh , You-Jin Jeon , Lai Ti Gew , Yoon-Yen Yow

Bioactive metabolites derived from algae are gaining popularity as safe and effective compounds for the development of new skincare products around the world. In this study, the cosmeceutical effects of Malaysian brown algae Sargassum aquifolium (S. aquifolium) extracts were investigated. The investigation began with phytochemical analysis and antioxidant activities. The anti-photoaging and anti-inflammation properties of S. aquifolium water and ethanol extracts were then tested against UVB-induced HaCaT keratinocytes and LPS-induced RAW 264.7 macrophages, respectively. S. aquifolium ethanol and water extracts are high in phenolic and flavonoid compounds and have high DPPH radical scavenging and reducing power activity. The ethanol extract was found to have remarkable anti-photoaging properties by downregulating COX-2 (1.2-fold) and MMP-1 (3.1-fold) expressions, as well as anti-inflammatory properties by suppressing iNOS via NO suppressions and inhibiting TNF-α (45%) and IL-6 secretion (98%). According to liquid chromatography-mass spectrometry (LC-MS) analysis S. aquifolium ethanol extract also contains carbohydrates, lipids, carotenoids, terpenes, pigments, benzofuran, and phloroglucinol. In conclusion, bioactive metabolites isolated from S. aquifolium ethanol extract have been shown to exhibit improved antioxidant, antiphotoaging, and anti-inflammatory capabilities, suggesting that they could be used as a cosmeceutical agent.

从藻类中提取的生物活性代谢物作为安全有效的化合物在世界各地越来越受欢迎，用于开发新的护肤品。本研究对马来西亚褐藻马尾藻（S. aquifolium）提取物的药妆作用进行了研究。调查从植物化学分析和抗氧化活性开始。然后分别对uvb诱导的HaCaT角质形成细胞和lps诱导的RAW 264.7巨噬细胞进行抗光老化和抗炎症的实验。水杨花乙醇和水提取物富含酚类和类黄酮化合物，具有很强的DPPH自由基清除和还原能力。通过下调COX-2（1.2倍）和MMP-1（3.1倍）的表达，发现乙醇提取物具有显著的抗光老化特性；通过抑制NO抑制iNOS，抑制TNF-α(45%)和IL-6分泌（98%），发现乙醇提取物具有显著的抗炎特性。根据液相色谱-质谱（LC-MS）分析，水杨花乙醇提取物还含有碳水化合物、脂类、类胡萝卜素、萜烯、色素、苯并呋喃和间苯三酚。综上所述，从水仙花乙醇提取物中分离出的生物活性代谢物具有较好的抗氧化、抗光老化和抗炎能力，可以作为药妆剂使用。

{"title":"Antiphotoaging and anti-inflammatory effects of Malaysian brown seaweed Sargassum aquifolium: Cellular insights from HaCaT and RAW 264.7 models and metabolite profiling via LC-MS","authors":"Krishnapriya Thiyagarasaiyar , Kai Xuan Lim , Chi Chen Wong , Jing Yu Lim , Bey-Hing Goh , You-Jin Jeon , Lai Ti Gew , Yoon-Yen Yow","doi":"10.1016/j.medidd.2025.100246","DOIUrl":"10.1016/j.medidd.2025.100246","url":null,"abstract":"<div><div>Bioactive metabolites derived from algae are gaining popularity as safe and effective compounds for the development of new skincare products around the world. In this study, the cosmeceutical effects of Malaysian brown algae <em>Sargassum aquifolium</em> (<em>S. aquifolium</em>) extracts were investigated. The investigation began with phytochemical analysis and antioxidant activities. The anti-photoaging and anti-inflammation properties of <em>S. aquifolium</em> water and ethanol extracts were then tested against UVB-induced HaCaT keratinocytes and LPS-induced RAW 264.7 macrophages, respectively. <em>S. aquifolium</em> ethanol and water extracts are high in phenolic and flavonoid compounds and have high DPPH radical scavenging and reducing power activity. The ethanol extract was found to have remarkable anti-photoaging properties by downregulating COX-2 (1.2-fold) and MMP-1 (3.1-fold) expressions, as well as anti-inflammatory properties by suppressing iNOS via NO suppressions and inhibiting TNF-α (45%) and IL-6 secretion (98%). According to liquid chromatography-mass spectrometry (LC-MS) analysis <em>S. aquifolium</em> ethanol extract also contains carbohydrates, lipids, carotenoids, terpenes, pigments, benzofuran, and phloroglucinol. In conclusion, bioactive metabolites isolated from <em>S. aquifolium</em> ethanol extract have been shown to exhibit improved antioxidant, antiphotoaging, and anti-inflammatory capabilities, suggesting that they could be used as a cosmeceutical agent.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100246"},"PeriodicalIF":0.0,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toward peptide-based protein replacement in fragile X syndrome: Evaluating the N-tat strategy 脆性X综合征中基于肽的蛋白质替代：评估N-tat策略

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-16 DOI: 10.1016/j.medidd.2025.100244

Oliver A. Kent

Fragile X syndrome (FXS), a leading inherited cause of intellectual disability and autism, arises from loss of the RNA-binding protein FMRP and consequent dysregulation of synaptic mRNA translation. No clinically approved therapies exist to restore FMRP function. A recent study showed that a Tat-conjugated FMRP fragment spanning residues 1–297 (FMRP N-tat) can transiently reduce hyperexcitability in an FXS mouse model, supporting peptide replacement as a feasible therapeutic strategy. Extending this concept, Leguay et al. demonstrated in FXS patient iPSC-derived neurons that N-tat reconstitutes interactions with endogenous protein partners correcting dysregulated translation and mitochondrial defects. However, despite recapitulating several functions of full-length FMRP, the in vivo effects of N-tat remain short-lived, highlighting challenges in stability and the potential need for additional functional domains. Herein, this commentary outlines both the promise of N-tat–based protein replacement and the remaining gaps that must be addressed to achieve clinically durable restoration of FMRP function.

脆性X染色体综合征（脆性X染色体综合征，FXS）是导致智力残疾和自闭症的主要遗传原因，它是由rna结合蛋白FMRP的缺失和由此导致的突触mRNA翻译失调引起的。目前还没有临床批准的治疗方法来恢复FMRP功能。最近的一项研究表明，tat偶联的跨越残基1-297的FMRP片段（FMRP N-tat）可以在FXS小鼠模型中短暂降低高兴奋性，支持肽替代作为一种可行的治疗策略。Leguay等人扩展了这一概念，在FXS患者ipsc衍生的神经元中证明，N-tat重建了与内源性蛋白伴侣的相互作用，纠正了翻译失调和线粒体缺陷。然而，尽管概述了全长FMRP的几个功能，但n -在体内的作用仍然是短暂的，这突出了稳定性方面的挑战和对其他功能域的潜在需求。在此，本文概述了基于n -tat的蛋白质替代的前景和必须解决的剩余空白，以实现临床持久的FMRP功能恢复。

引用次数: 0

3D printing in drug delivery: emerging technologies, clinical translation, and the future of personalized medicine 3D打印在药物输送：新兴技术，临床翻译，和个性化医疗的未来

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-13 DOI: 10.1016/j.medidd.2025.100242

Bellarmin Michael, Nandhini Jayaprakash, Nithyasree Munivel, Dharshini Jaisankar

Three-dimensional (3D) printing has rapidly evolved into a transformative platform for drug delivery, offering capabilities that extend far beyond the customization possible with traditional manufacturing. This review critically evaluates the major 3D-printing technologies FDM, SLS, SLA/CLIP, SSE, and multi-material inkjet and compares their suitability across oral, transdermal, implantable, and bioprinted systems. Emphasis is placed on material limitations, polymer–drug compatibility challenges, quality-control constraints, and regulatory barriers that currently restrict translation. Recent advancements in nano-enabled formulations, stimuli-responsive architectures, and high-resolution multi-material systems are examined to illustrate how structural design directly influences pharmacokinetics and therapeutic performance. The review concludes with a forward-looking synthesis that highlights emerging opportunities in AI-assisted dosage design, 4D shape-morphing platforms, and point-of-care manufacturing workflows. Together, these insights provide a comprehensive and critical understanding of the technological, material, and regulatory factors shaping the future of 3D-printed drug delivery. By advancing innovation in pharmaceutical manufacturing and enabling more equitable access to personalized therapies, 3D printing represents a pivotal evolution toward patient-centric drug delivery solutions.

三维（3D）打印已经迅速发展成为一个变革性的药物输送平台，提供的功能远远超出了传统制造的定制化。本文对FDM、SLS、SLA/CLIP、SSE和多材料喷墨等主要3d打印技术进行了批判性评估，并比较了它们在口腔、透皮、植入式和生物打印系统中的适用性。重点放在材料限制、聚合物药物相容性挑战、质量控制约束和目前限制翻译的监管障碍上。研究了纳米配方、刺激响应结构和高分辨率多材料系统的最新进展，以说明结构设计如何直接影响药代动力学和治疗性能。该综述总结了一个前瞻性的综合，强调了人工智能辅助剂量设计、4D形状变形平台和护理点制造工作流程中的新兴机会。总之，这些见解提供了对影响3d打印给药未来的技术、材料和监管因素的全面和批判性理解。通过推动制药制造的创新和实现更公平的个性化治疗，3D打印代表了以患者为中心的药物输送解决方案的关键演变。

{"title":"3D printing in drug delivery: emerging technologies, clinical translation, and the future of personalized medicine","authors":"Bellarmin Michael, Nandhini Jayaprakash, Nithyasree Munivel, Dharshini Jaisankar","doi":"10.1016/j.medidd.2025.100242","DOIUrl":"10.1016/j.medidd.2025.100242","url":null,"abstract":"<div><div>Three-dimensional (3D) printing has rapidly evolved into a transformative platform for drug delivery, offering capabilities that extend far beyond the customization possible with traditional manufacturing. This review critically evaluates the major 3D-printing technologies FDM, SLS, SLA/CLIP, SSE, and multi-material inkjet and compares their suitability across oral, transdermal, implantable, and bioprinted systems. Emphasis is placed on material limitations, polymer–drug compatibility challenges, quality-control constraints, and regulatory barriers that currently restrict translation. Recent advancements in nano-enabled formulations, stimuli-responsive architectures, and high-resolution multi-material systems are examined to illustrate how structural design directly influences pharmacokinetics and therapeutic performance. The review concludes with a forward-looking synthesis that highlights emerging opportunities in AI-assisted dosage design, 4D shape-morphing platforms, and point-of-care manufacturing workflows. Together, these insights provide a comprehensive and critical understanding of the technological, material, and regulatory factors shaping the future of 3D-printed drug delivery. By advancing innovation in pharmaceutical manufacturing and enabling more equitable access to personalized therapies, 3D printing represents a pivotal evolution toward patient-centric drug delivery solutions.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100242"},"PeriodicalIF":0.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145790691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Machine learning based analysis of the risks of combination aspirin and rivaroxabane antithrombotic therapy with nonsteroid anti-inflammatory drugs after arthroplasty 基于机器学习的人工关节置换术后阿司匹林和利伐沙巴联合抗血栓治疗与非甾体抗炎药的风险分析

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-09 DOI: 10.1016/j.medidd.2025.100243

Vladimir U. Emelianov , Sergey A. Khripunov , Evgeniya A. Mikishanina , Nikolai S. Nikolaev

Objective

Thromboprophylaxis is essential following major joint surgery. While aspirin is widely discussed as a postoperative prophylactic alternative to heparin or rivaroxaban, it is often co-administered with NSAIDs for pain relief. The safety of such combinations remains unclear. This study uses multivariate machine learning (ML) analysis to compare bleeding risks between aspirin and rivaroxaban, and between their respective combinations with ketorolac or celecoxib.

Methods

We conducted a retrospective study of 1164 patients who underwent primary total knee or joint arthroplasty. ML was applied to model the risk of bleeding based on the clinical factors.

Results

The analysis revealed a minimal difference in bleeding risk between aspirin (odds ratio [OR] = 1.042, 95 % confidence interval [CI] = 0.762–1.426, 1.000) and rivaroxaban (OR = 0.959, 95 % CI = 0.701–1.312, p = 1.000). Concomitant use of ketorolac with either anticoagulant non-significantly increased the risk of bleeding (OR = 1.077, 95 % CI = 0.787–1.473, p = 0.337), in contrast, the combination with celecoxib was associated with a reduced risk (OR = 0.751, 95 % CI = 0.549–1.028, p = 0.0008). Multivariable logistic regression demonstrated the highest predictive value (AUC = 0.68), along with the best F1 score and Matthews correlation coefficient (0.32 and 0.22, respectively).

Conclusion

Aspirin and rivaroxaban appear to be interchangeable with respect to bleeding risk. While combining these anticoagulants with ketorolac did not significantly affect bleeding risk, the combination with celecoxib was associated with a lower risk. Therefore celecoxib may be preferable NSAID for analgesia in this context.

目的：大关节手术后血栓预防是必要的。虽然阿司匹林作为术后肝素或利伐沙班的预防性替代品被广泛讨论，但它通常与非甾体抗炎药共同使用以缓解疼痛。这种组合的安全性尚不清楚。本研究使用多变量机器学习（ML）分析来比较阿司匹林和利伐沙班之间的出血风险，以及它们各自与酮罗拉酸或塞来昔布的组合之间的出血风险。方法对1164例接受全膝关节或关节置换术的患者进行回顾性研究。基于临床因素，应用ML建立出血风险模型。结果分析显示阿司匹林与利伐沙班在出血风险方面差异极小（比值比[OR] = 1.042, 95%可信区间[CI] = 0.762-1.426, 1.000）（OR = 0.959, 95% CI = 0.701-1.312, p = 1.000）。酮咯酸与任何一种抗凝剂合用均未显著增加出血风险（OR = 1.077, 95% CI = 0.787-1.473, p = 0.337），而与塞来昔布合用则降低出血风险（OR = 0.751, 95% CI = 0.549-1.028, p = 0.0008）。多变量logistic回归的预测值最高（AUC = 0.68）， F1得分和Matthews相关系数最高（分别为0.32和0.22）。结论阿司匹林与利伐沙班在出血风险方面具有互换性。虽然这些抗凝剂与酮咯酸联合使用对出血风险没有显著影响，但与塞来昔布联合使用的风险较低。因此，在这种情况下，塞来昔布可能是更好的非甾体抗炎药。

{"title":"Machine learning based analysis of the risks of combination aspirin and rivaroxabane antithrombotic therapy with nonsteroid anti-inflammatory drugs after arthroplasty","authors":"Vladimir U. Emelianov , Sergey A. Khripunov , Evgeniya A. Mikishanina , Nikolai S. Nikolaev","doi":"10.1016/j.medidd.2025.100243","DOIUrl":"10.1016/j.medidd.2025.100243","url":null,"abstract":"<div><h3>Objective</h3><div>Thromboprophylaxis is essential following major joint surgery. While aspirin is widely discussed as a postoperative prophylactic alternative to heparin or rivaroxaban, it is often co-administered with NSAIDs for pain relief. The safety of such combinations remains unclear. This study uses multivariate machine learning (ML) analysis to compare bleeding risks between aspirin and rivaroxaban, and between their respective combinations with ketorolac or celecoxib.</div></div><div><h3>Methods</h3><div>We conducted a retrospective study of 1164 patients who underwent primary total knee or joint arthroplasty. ML was applied to model the risk of bleeding based on the clinical factors.</div></div><div><h3>Results</h3><div>The analysis revealed a minimal difference in bleeding risk between aspirin (odds ratio [OR] = 1.042, 95 % confidence interval [CI] = 0.762–1.426, 1.000) and rivaroxaban (OR = 0.959, 95 % CI = 0.701–1.312, p = 1.000). Concomitant use of ketorolac with either anticoagulant non-significantly increased the risk of bleeding (OR = 1.077, 95 % CI = 0.787–1.473, p = 0.337), in contrast, the combination with celecoxib was associated with a reduced risk (OR = 0.751, 95 % CI = 0.549–1.028, p = 0.0008). Multivariable logistic regression demonstrated the highest predictive value (AUC = 0.68), along with the best F1 score and Matthews correlation coefficient (0.32 and 0.22, respectively).</div></div><div><h3>Conclusion</h3><div>Aspirin and rivaroxaban appear to be interchangeable with respect to bleeding risk. While combining these anticoagulants with ketorolac did not significantly affect bleeding risk, the combination with celecoxib was associated with a lower risk. Therefore celecoxib may be preferable NSAID for analgesia in this context.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100243"},"PeriodicalIF":0.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of α-glucosidase by melatonin derivatives: insights from kinetics, docking, and molecular dynamics simulations 褪黑素衍生物对α-葡萄糖苷酶的抑制作用：来自动力学、对接和分子动力学模拟的见解

Q2 Medicine

Medicine in Drug Discovery

Pub Date : 2025-12-04 DOI: 10.1016/j.medidd.2025.100240

Ploenthip Puthongking , Bodee Nutho , Muhammad Subhan , Juthamat Ratha , Kiattawee Choowongkomon , Saranyu Khammuang , Kamonpan Sanachai

Type 2 diabetes mellitus (T2DM) represents a major global health challenge, emphasizing the need for effective strategies to manage postprandial hyperglycemia. Inhibition of α-glucosidase, a key enzyme involved in carbohydrate digestion, is a well-established therapeutic approach. In this study, melatonin, an indoleamine with diverse biological activities, was investigated as a scaffold for the development of novel α-glucosidase inhibitors. Among the derivatives evaluated, 4EBM emerged as the most potent inhibitor, exhibiting an IC₅₀ value of 37.20 ± 0.64 μM and demonstrating greater potency than the standard drug, acarbose. Kinetic studies, molecular docking, and molecular dynamics (MD) simulations indicated that 4EBM acts as a competitive inhibitor by directly interacting with key residues (Y158, F178, Q279, R315, and R442) within the α-glucosidase active site. Furthermore, in silico predictions suggested that several derivatives containing naphthalene, biphenyl, or trifluoromethylphenyl moieties exhibited stronger binding affinities than 4EBM. These findings underscore the potential of melatonin derivatives as promising lead compounds for the development of more effective α-glucosidase inhibitors for T2DM management, while also enhancing the current understanding of indoleamine scaffolds in enzyme inhibition.

2型糖尿病（T2DM）是一个重大的全球健康挑战，强调需要有效的策略来控制餐后高血糖。α-葡萄糖苷酶是参与碳水化合物消化的关键酶，抑制α-葡萄糖苷酶是一种公认的治疗方法。在本研究中，褪黑素作为一种具有多种生物活性的吲哚胺，被研究作为开发新型α-葡萄糖苷酶抑制剂的支架。结果表明，4EBM的IC50值为37.20±0.64 μM，比阿卡波糖更有效。动力学研究、分子对接和分子动力学（MD）模拟表明，4EBM通过与α-葡萄糖苷酶活性位点的关键残基（Y158、F178、Q279、R315和R442）直接相互作用而发挥竞争性抑制剂的作用。此外，计算机预测表明，几种含有萘、联苯或三氟甲基苯基基团的衍生物比4EBM具有更强的结合亲和力。这些发现强调了褪黑素衍生物作为开发更有效的α-葡萄糖苷酶抑制剂用于T2DM治疗的有前途的先导化合物的潜力，同时也增强了目前对吲哚胺支架在酶抑制中的理解。

{"title":"Inhibition of α-glucosidase by melatonin derivatives: insights from kinetics, docking, and molecular dynamics simulations","authors":"Ploenthip Puthongking , Bodee Nutho , Muhammad Subhan , Juthamat Ratha , Kiattawee Choowongkomon , Saranyu Khammuang , Kamonpan Sanachai","doi":"10.1016/j.medidd.2025.100240","DOIUrl":"10.1016/j.medidd.2025.100240","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) represents a major global health challenge, emphasizing the need for effective strategies to manage postprandial hyperglycemia. Inhibition of α-glucosidase, a key enzyme involved in carbohydrate digestion, is a well-established therapeutic approach. In this study, melatonin, an indoleamine with diverse biological activities, was investigated as a scaffold for the development of novel α-glucosidase inhibitors. Among the derivatives evaluated, 4EBM emerged as the most potent inhibitor, exhibiting an IC<sub>50</sub> value of 37.20 ± 0.64 μM and demonstrating greater potency than the standard drug, acarbose. Kinetic studies, molecular docking, and molecular dynamics (MD) simulations indicated that 4EBM acts as a competitive inhibitor by directly interacting with key residues (Y158, F178, Q279, R315, and R442) within the α-glucosidase active site. Furthermore, <em>in silico</em> predictions suggested that several derivatives containing naphthalene, biphenyl, or trifluoromethylphenyl moieties exhibited stronger binding affinities than 4EBM. These findings underscore the potential of melatonin derivatives as promising lead compounds for the development of more effective α-glucosidase inhibitors for T2DM management, while also enhancing the current understanding of indoleamine scaffolds in enzyme inhibition.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"29 ","pages":"Article 100240"},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0