Pub Date : 2025-09-26DOI: 10.1016/j.medidd.2025.100231
Shaoxin Huang , Shiyu Wang , Junlin Dong , Marc Xu , Shuguang Yuan
Bioisosteric replacement is an important method for rational drug design. It enables the modification of key pharmacophores or functional groups to achieve desired molecular properties. However, systematic collections and updates in this method are missing at present. Here, we introduce NeBULA (Next-Generation Bioisostere Utility Libraries), which systematically collects, organizes, and checks qualitative bioisosteric replacements from more than 700 authoritative medicinal chemistry references. Based on this large database, we developed a user-friendly online drug optimization tool. It not only provides up-to-date alternatives for bioisosteric replacement from experimental data, but also resolves noticeable issues in current tools. Furthermore, NeBULA provides Fsp3-rich bioisosteric replacement SMARTS (SMIRKS) reactions, as well as a library full of drug-like molecules and fragments. Finally, the molecular fragmentation applications inside NeBULA platform offer medicinal chemists numerous fragments for drug fusion and replacement. NeBULA is freely available via the following webpage: http://nebula.alphamol.com.cn:5001.
{"title":"NeBULA: a web-based novel drug design platform for up-to-date bioisosteric replacement","authors":"Shaoxin Huang , Shiyu Wang , Junlin Dong , Marc Xu , Shuguang Yuan","doi":"10.1016/j.medidd.2025.100231","DOIUrl":"10.1016/j.medidd.2025.100231","url":null,"abstract":"<div><div>Bioisosteric replacement is an important method for rational drug design. It enables the modification of key pharmacophores or functional groups to achieve desired molecular properties. However, systematic collections and updates in this method are missing at present. Here, we introduce NeBULA (Next-Generation Bioisostere Utility Libraries), which systematically collects, organizes, and checks qualitative bioisosteric replacements from more than 700 authoritative medicinal chemistry references. Based on this large database, we developed a user-friendly online drug optimization tool. It not only provides up-to-date alternatives for bioisosteric replacement from experimental data, but also resolves noticeable issues in current tools. Furthermore, NeBULA provides Fsp<sup>3</sup>-rich bioisosteric replacement SMARTS (SMIRKS) reactions, as well as a library full of drug-like molecules and fragments. Finally, the molecular fragmentation applications inside NeBULA platform offer medicinal chemists numerous fragments for drug fusion and replacement. NeBULA is freely available via the following webpage: <span><span>http://nebula.alphamol.com.cn:5001</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100231"},"PeriodicalIF":0.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145219777","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}
Pub Date : 2025-09-24DOI: 10.1016/j.medidd.2025.100230
Md Khalid Saifullah, Ahasan, Mohammad Kaleem, Elaf Raneem, Amisha Gupta, Mohd Amir, M. Mumtaz Alam, Mymoona Akhter, Sharba Tasneem, M. Shaquiquzzaman
Cancer is still one of the world’s leading causes of mortality and developing effective therapies for it is extremely difficult. An ongoing study is dedicated to identifying suitable medicinal agents for cancer therapy. Among these, Chalcones are one of the components that have attracted a lot of attention because of their unique and varied pharmacological characteristics. Across a range of cancer types, several chalcone compounds have shown encouraging anticancer efficacy. This review covers current breakthroughs in the research of natural and synthesized chalcones with anticancer potential. It examines chalcones that target specific enzymes involved in cancer treatment, discusses their structure–activity relationships, docking studies were carried out on target-specific proteins (PDB IDs) and presents the structures of the most promising compounds together with their biological activities.The impressive results showcased by these chalcone-based scaffolds position them as leading contenders in the search for new anticancer drug candidates, offering valuable insights for researchers focused on synthesizing novel therapeutic agents.
{"title":"A comprehensive review of structure activity relationships: exploration of chalcone derivatives as anticancer agents, target-based and cell line-specific insights","authors":"Md Khalid Saifullah, Ahasan, Mohammad Kaleem, Elaf Raneem, Amisha Gupta, Mohd Amir, M. Mumtaz Alam, Mymoona Akhter, Sharba Tasneem, M. Shaquiquzzaman","doi":"10.1016/j.medidd.2025.100230","DOIUrl":"10.1016/j.medidd.2025.100230","url":null,"abstract":"<div><div>Cancer is still one of the world’s leading causes of mortality and developing effective therapies for it is extremely difficult. An ongoing study is dedicated to identifying suitable medicinal agents for cancer therapy. Among these, Chalcones are one of the components that have attracted a lot of attention because of their unique and varied pharmacological characteristics. Across a range of cancer types, several chalcone compounds have shown encouraging anticancer efficacy. This review covers current breakthroughs in the research of natural and synthesized chalcones with anticancer potential. It examines chalcones that target specific enzymes involved in cancer treatment, discusses their structure–activity relationships, docking studies were carried out on target-specific proteins (PDB IDs) and presents the structures of the most promising compounds together with their biological activities.The impressive results showcased by these chalcone-based scaffolds position them as leading contenders in the search for new anticancer drug candidates, offering valuable insights for researchers focused on synthesizing novel therapeutic agents.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100230"},"PeriodicalIF":0.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158333","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}
Pub Date : 2025-09-20DOI: 10.1016/j.medidd.2025.100226
Wenxin Li , Quanxiao Li , Qingtong Zhou , Yanling Wu , Ming-Wei Wang , Tianlei Ying
Tumor-infiltrating regulatory T (Ti-Treg) cells play a pivotal role in suppressing antitumor immune responses within tumor microenvironment. Targeted depletion of Treg cells has emerged as a promising strategy to enhance antitumor immunity. However, current approaches such as antibody-drug conjugates (ADCs) that target a single Treg-associated antigen often suffer from limited specificity and efficacy. Here, we developed four formats of bispecific antibodies (BsAbs) targeting mouse C–C motif chemokine receptor 8 (CCR8) and tumor necrosis factor receptor 2 (TNFR2), two surface markers predominantly expressed on Treg cells. These BsAbs were efficiently expressed with retained high-affinity binding to both antigens. By conjugation with pyrrolobenzodiazepine (PBD) dimer payload using a cleavable linker, the resulting bispecific ADCs (BsADCs) exhibited potent cytotoxic activity in vivo. In murine syngeneic tumor models, BsADCs significantly suppressed tumor growth and exhibited superior therapeutic efficacy over monospecific ADCs, achieving complete tumor regression in 4 out of 5 mice (80%). Collectively, our findings have established a BsADC-based strategy for selective Treg depletion, providing a novel immunotherapeutic approach for solid tumors.
{"title":"A bispecific ADC against CCR8 and TNFR2 elicits potent antitumor efficacy","authors":"Wenxin Li , Quanxiao Li , Qingtong Zhou , Yanling Wu , Ming-Wei Wang , Tianlei Ying","doi":"10.1016/j.medidd.2025.100226","DOIUrl":"10.1016/j.medidd.2025.100226","url":null,"abstract":"<div><div>Tumor-infiltrating regulatory T (Ti-Treg) cells play a pivotal role in suppressing antitumor immune responses within tumor microenvironment. Targeted depletion of Treg cells has emerged as a promising strategy to enhance antitumor immunity. However, current approaches such as antibody-drug conjugates (ADCs) that target a single Treg-associated antigen often suffer from limited specificity and efficacy. Here, we developed four formats of bispecific antibodies (BsAbs) targeting mouse C–C motif chemokine receptor 8 (CCR8) and tumor necrosis factor receptor 2 (TNFR2), two surface markers predominantly expressed on Treg cells. These BsAbs were efficiently expressed with retained high-affinity binding to both antigens. By conjugation with pyrrolobenzodiazepine (PBD) dimer payload using a cleavable linker, the resulting bispecific ADCs (BsADCs) exhibited potent cytotoxic activity <em>in vivo</em>. In murine syngeneic tumor models, BsADCs significantly suppressed tumor growth and exhibited superior therapeutic efficacy over monospecific ADCs, achieving complete tumor regression in 4 out of 5 mice (80%). Collectively, our findings have established a BsADC-based strategy for selective Treg depletion, providing a novel immunotherapeutic approach for solid tumors.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100226"},"PeriodicalIF":0.0,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158334","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}
Pub Date : 2025-09-19DOI: 10.1016/j.medidd.2025.100229
Yuan Li , Yanxin Zhang , Guanqun Wan , Shaofei Song , Tingting Zhao , Renjie Cao , Weiwei Zeng , Min Huang , Yiming Jiang
Objective
18β-Glycyrrhetinic acid (18β-GA), a key bioactive triterpenoid in Glycyrrhiza uralensis Fisch, is recognized for its hepatoprotective effects in liver injury. However, the effect of 18β-GA on liver regeneration after partial hepatectomy (PHx) remains unknown. This study aims to investigate the effects and underlying mechanisms of 18β-GA in facilitating liver regeneration after PHx.
Methods
PHx mice were orally gavaged with 18β-GA for 7 days. The promotion of 18β-GA on liver regeneration was evaluated by liver/body weight ratio, BrdU, Ki67 and PCNA. Cell cycle transition was performed to evaluate hepatocyte proliferation. The effects of 18β-GA on protein and mRNA expression levels within the MAPK/ERK signaling pathway were systematically evaluated.
Results
18β-GA significantly accelerated liver mass recovery and promoted hepatocyte proliferation after PHx. 18β-GA treatment facilitated the cellular G1/S phase transition and upregulated the expression of the proliferation-related protein CCND1, PCNA, and p-RB. Moreover, 18β-GA significantly increased the levels of growth factors including Hgf, Egf, Tgf-α, and Hb-egf. Furthermore, mechanistic investigations suggested that 18β-GA activated the MAPK/ERK signaling pathway, increasing the expression of p-ERK1/2, c-JUN, c-FOS, and c-MYC in vitro and in vivo. Application of ERK inhibitor U0126 effectively abolished 18β-GA-induced activation of MAPK/ERK signaling pathway.
Conclusion
18β-GA exhibited a significant promoting effect on liver recovery following PHx, potentially through modulation of the MAPK/ERK signaling pathway to accelerate liver regeneration.
{"title":"18β-glycyrrhetinic acid accelerates liver regeneration after partial hepatectomy in mice","authors":"Yuan Li , Yanxin Zhang , Guanqun Wan , Shaofei Song , Tingting Zhao , Renjie Cao , Weiwei Zeng , Min Huang , Yiming Jiang","doi":"10.1016/j.medidd.2025.100229","DOIUrl":"10.1016/j.medidd.2025.100229","url":null,"abstract":"<div><h3>Objective</h3><div>18β-Glycyrrhetinic acid (18β-GA), a key bioactive triterpenoid in <em>Glycyrrhiza uralensis</em> Fisch, is recognized for its hepatoprotective effects in liver injury. However, the effect of 18β-GA on liver regeneration after partial hepatectomy (PHx) remains unknown. This study aims to investigate the effects and underlying mechanisms of 18β-GA in facilitating liver regeneration after PHx.</div></div><div><h3>Methods</h3><div>PHx mice were orally gavaged with 18β-GA for 7 days. The promotion of 18β-GA on liver regeneration was evaluated by liver/body weight ratio, BrdU, Ki67 and PCNA. Cell cycle transition was performed to evaluate hepatocyte proliferation. The effects of 18β-GA on protein and mRNA expression levels within the MAPK/ERK signaling pathway were systematically evaluated.</div></div><div><h3>Results</h3><div>18β-GA significantly accelerated liver mass recovery and promoted hepatocyte proliferation after PHx. 18β-GA treatment facilitated the cellular G1/S phase transition and upregulated the expression of the proliferation-related protein CCND1, PCNA, and p-RB. Moreover, 18β-GA significantly increased the levels of growth factors including <em>Hgf</em>, <em>Egf</em>, <em>Tgf-α,</em> and <em>Hb-egf</em>. Furthermore, mechanistic investigations suggested that 18β-GA activated the MAPK/ERK signaling pathway, increasing the expression of p-ERK1/2, c-JUN, c-FOS, and c-MYC <em>in vitro</em> and <em>in vivo</em>. Application of ERK inhibitor U0126 effectively abolished 18β-GA-induced activation of MAPK/ERK signaling pathway.</div></div><div><h3>Conclusion</h3><div>18β-GA exhibited a significant promoting effect on liver recovery following PHx, potentially through modulation of the MAPK/ERK signaling pathway to accelerate liver regeneration.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100229"},"PeriodicalIF":0.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118683","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}
Pub Date : 2025-09-14DOI: 10.1016/j.medidd.2025.100228
Vikas Kumar , Aditi Singh , Nitin Sharma , Rakshandha Saini , Harsh Kumar , Mohamed El–Shazly , Kamal Dev
The global effort to combat multidrug resistance (MDR) has placed a significant economic burden on countries across the world. Antibiotics, celebrated throughout the 20th century for their remarkable ability to treat infectious diseases, have been compromised by their misuse and overuse, leading to the widespread emergence of antimicrobial resistance. Consequently, there is growing interest in plant-based solutions, as approximately 30–50% of existing drugs are derived from medicinal plants. This review explores the potential of plants, which produce a wide range of secondary metabolites, to provide novel antibiotics that can address bacterial resistance. We also discuss the processes via which phytocompounds (synonymous with phytoceuticals) assist in overcoming the increase in resistance and strategies in combining them with conventional antibiotics to prevent the life-threatening consequences of multidrug resistance. Additionally, challenges and safety concerns regarding the utilization of phytocompounds in MDR treatment are also discussed.
{"title":"Combating bacterial antibiotic resistance with phytocompounds: Current trends and future perspectives","authors":"Vikas Kumar , Aditi Singh , Nitin Sharma , Rakshandha Saini , Harsh Kumar , Mohamed El–Shazly , Kamal Dev","doi":"10.1016/j.medidd.2025.100228","DOIUrl":"10.1016/j.medidd.2025.100228","url":null,"abstract":"<div><div>The global effort to combat multidrug resistance (MDR) has placed a significant economic burden on countries across the world. Antibiotics, celebrated throughout the 20th century for their remarkable ability to treat infectious diseases, have been compromised by their misuse and overuse, leading to the widespread emergence of antimicrobial resistance. Consequently, there is growing interest in plant-based solutions, as approximately 30–50% of existing drugs are derived from medicinal plants. This review explores the potential of plants, which produce a wide range of secondary metabolites, to provide novel antibiotics that can address bacterial resistance. We also discuss the processes via which phytocompounds (synonymous with phytoceuticals) assist in overcoming the increase in resistance and strategies in combining them with conventional antibiotics to prevent the life-threatening consequences of multidrug resistance. Additionally, challenges and safety concerns regarding the utilization of phytocompounds in MDR treatment are also discussed.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100228"},"PeriodicalIF":0.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060092","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}
Pub Date : 2025-09-13DOI: 10.1016/j.medidd.2025.100227
Deepali M. Wanode , Pramod B. Khedekar
VEGFR-2 imparts main role in angiogenesis and tumor progression, establishing it as a crucial target in anticancer drug discovery. Pyrazole is a versatile moiety with broad spectrum of biological activities, notably anticancer potential. This review highlights recent progress in the development of pyrazole-based compounds, an overview of the available methodologies for the synthesis and biological evaluation as potent VEGFR-2 kinase inhibitors. A comprehensive SAR analysis is presented to elucidate key molecular modifications that enhance anticancer efficacy. Particular focus is given to substitution patterns on the pyrazole ring and the integration of hybrid pharmacophores to improve target selectivity and overall biological performance. Furthermore, molecular docking studies and cytotoxicity evaluations against various cancer cell lines are discussed to support the therapeutic relevance of these compounds. Collectively, the findings underscore pyrazole derivatives as promising candidates for the development of future anticancer agents targeting VEGFR-2 kinase.
{"title":"Synthetic advances and SAR insights of pyrazole-based VEGFR-2 kinase inhibitors","authors":"Deepali M. Wanode , Pramod B. Khedekar","doi":"10.1016/j.medidd.2025.100227","DOIUrl":"10.1016/j.medidd.2025.100227","url":null,"abstract":"<div><div>VEGFR-2 imparts main role in angiogenesis and tumor progression, establishing it as a crucial target in anticancer drug discovery. Pyrazole is a versatile moiety with broad spectrum of biological activities, notably anticancer potential. This review highlights recent progress in the development of pyrazole-based compounds, an overview of the available methodologies for the synthesis and biological evaluation as potent VEGFR-2 kinase inhibitors. A comprehensive SAR analysis is presented to elucidate key molecular modifications that enhance anticancer efficacy. Particular focus is given to substitution patterns on the pyrazole ring and the integration of hybrid pharmacophores to improve target selectivity and overall biological performance. Furthermore, molecular docking studies and cytotoxicity evaluations against various cancer cell lines are discussed to support the therapeutic relevance of these compounds. Collectively, the findings underscore pyrazole derivatives as promising candidates for the development of future anticancer agents targeting VEGFR-2 kinase.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100227"},"PeriodicalIF":0.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145105567","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}
The fusion of Artificial intelligence (AI) with computational chemistry has revolutionized drug discovery by enhancing compound optimization, predictive analytics, and molecular modeling. This review explores the integration of AI techniques, including machine learning (ML), deep learning (DL), and generative models with traditional computational methods such as molecular docking, quantum mechanics, and molecular dynamics simulations. It outlines the evolution of computational chemistry and the transformative role of AI in interpreting complex molecular data, automating feature extraction, and improving decision-making across the drug development pipeline. Core AI algorithms support vector machines, random forests, graph neural networks, and transformers are examined for their applications in molecular representation, virtual screening, and ADMET property prediction. Special attention is given to de novo drug design using generative adversarial networks (GANs) and variational autoencoders (VAEs), as well as AI-driven high-throughput virtual screening that reduces computational costs while improving hit identification. The review also discusses platforms like Deep-PK and DeepTox for pharmacokinetics and toxicity prediction using graph-based descriptors and multitask learning. In structure-based design, AI-enhanced scoring functions and binding affinity models outperform classical approaches, while DL transforms molecular dynamics by approximating force fields and capturing conformational dynamics. The convergence of AI with quantum chemistry and density functional theory (DFT) is illustrated through surrogate modeling and reaction mechanism prediction. Despite these advances, challenges remain in data quality, model interpretability, and generalizability. The review concludes by highlighting future directions, including hybrid AI-quantum frameworks and multi-omics integration, underscoring AI’s potential to accelerate safer, more cost-effective drug discovery.
{"title":"Revolutionizing pharmacology: AI-powered approaches in molecular modeling and ADMET prediction","authors":"Irfan Pathan , Arif Raza , Adarsh Sahu , Mohit Joshi , Yamini Sahu , Yash Patil , Mohammad Adnan Raza , Ajazuddin","doi":"10.1016/j.medidd.2025.100223","DOIUrl":"10.1016/j.medidd.2025.100223","url":null,"abstract":"<div><div>The fusion of Artificial intelligence (AI) with computational chemistry has revolutionized drug discovery by enhancing compound optimization, predictive analytics, and molecular modeling. This review explores the integration of AI techniques, including machine learning (ML), deep learning (DL), and generative models with traditional computational methods such as molecular docking, quantum mechanics, and molecular dynamics simulations. It outlines the evolution of computational chemistry and the transformative role of AI in interpreting complex molecular data, automating feature extraction, and improving decision-making across the drug development pipeline. Core AI algorithms support vector machines, random forests, graph neural networks, and transformers are examined for their applications in molecular representation, virtual screening, and ADMET property prediction. Special attention is given to de novo drug design using generative adversarial networks (GANs) and variational autoencoders (VAEs), as well as AI-driven high-throughput virtual screening that reduces computational costs while improving hit identification. The review also discusses platforms like Deep-PK and DeepTox for pharmacokinetics and toxicity prediction using graph-based descriptors and multitask learning. In structure-based design, AI-enhanced scoring functions and binding affinity models outperform classical approaches, while DL transforms molecular dynamics by approximating force fields and capturing conformational dynamics. The convergence of AI with quantum chemistry and density functional theory (DFT) is illustrated through surrogate modeling and reaction mechanism prediction. Despite these advances, challenges remain in data quality, model interpretability, and generalizability. The review concludes by highlighting future directions, including hybrid AI-quantum frameworks and multi-omics integration, underscoring AI’s potential to accelerate safer, more cost-effective drug discovery.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100223"},"PeriodicalIF":0.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144885771","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}
Pub Date : 2025-08-18DOI: 10.1016/j.medidd.2025.100224
Kai-feng He , Hao-dong Cui , Wen-hui Deng , Na Xing , Guo-jian Liu , Abdallah Iddy Chaurembo , Li-dan Fu , Yuan Li , Xin-yue Tong , Han-bin Lin , Chun-he Wang
Background
Monoclonal antibodies (mAbs) are typically colorless; however, the pink coloration observed during production raises quality concerns. This study investigated the mechanism linking this color change to Vitamin B12 (VB12), which converts to hydroxycobalamin (OH-Cbl) under light and binds covalently to cysteine residues in antibodies via cobalt-sulfur bonds.
Methods
Three batches of IgG1 antibodies (SP1, SP2, and NL)—were expressed in CHO cells, exposed to light, and purified. Binding interactions were analyzed using HPLC, RP-UPLC/MS, SDS-PAGE, and hydrophobic interaction chromatography (HIC). Peptide mapping and 3D structural modeling using protenix and autodock vina software identified the binding sites and spatial requirements.
Results
OH-Cbl covalently binds to five cysteine residues: L_Csy138 and L_Csy218 (light chain) and H_Csy22, H_Csy96, and H_Csy323 (heavy chain). SP2 exhibited a higher VB12 content (molar ratio 1:5.71 vs. 1:9.74 in SP1) and increased hydrophobicity, confirming covalent attachment. Structural modeling revealed large protein pockets around these cysteines, accommodating VB12′s bulky structure. Peptide analysis revealed distinct UV absorption at 360 nm for SP2, while SDS-PAGE indicated slight molecular weight differences.
Conclusion
The pink coloration arises from the light-induced conversion of VB12 to OH-Cbl, which binds covalently to specific cysteine residues, facilitated by spatially permissive protein pockets. Controlling the light exposure during production can mitigate this phenomenon. This study elucidates the structural basis of antibody-VB12 interactions, offering critical insights for optimizing mAb quality control.
单克隆抗体（mab）通常是无色的；然而，在生产过程中观察到的粉红色引起了质量问题。本研究探讨了将这种颜色变化与维生素B12 （VB12）联系起来的机制，维生素B12在光线下转化为羟基钴胺素（OH-Cbl），并通过钴硫键与抗体中的半胱氨酸残基共价结合。方法在CHO细胞中表达3批IgG1抗体（SP1、SP2和NL），经光照纯化。采用HPLC、RP-UPLC/MS、SDS-PAGE和疏水相互作用色谱（HIC）分析结合相互作用。利用protenix和autodock vina软件进行肽图绘制和三维结构建模，确定了结合位点和空间要求。结果soh - cbl共价结合5个半胱氨酸残基：L_Csy138、L_Csy218（轻链）和H_Csy22、H_Csy96、H_Csy323（重链）。SP2表现出更高的VB12含量（摩尔比1:5.71 vs. 1:9.74）和更高的疏水性，证实了共价附着。结构模型显示，这些半胱氨酸周围有大的蛋白质口袋，可以容纳VB12的庞大结构。肽分析显示SP2在360 nm处有明显的紫外吸收，而SDS-PAGE显示其分子量略有差异。结论VB12在光诱导下转化为OH-Cbl， OH-Cbl与特定的半胱氨酸残基共价结合，在空间允许的蛋白口袋的促进下呈现粉红色。在生产过程中控制光照可以缓解这种现象。本研究阐明了抗体- vb12相互作用的结构基础，为优化单抗质量控制提供了重要见解。
{"title":"From colorless to pink: Structural insights into vitamin B12-induced color change in monoclonal antibodies","authors":"Kai-feng He , Hao-dong Cui , Wen-hui Deng , Na Xing , Guo-jian Liu , Abdallah Iddy Chaurembo , Li-dan Fu , Yuan Li , Xin-yue Tong , Han-bin Lin , Chun-he Wang","doi":"10.1016/j.medidd.2025.100224","DOIUrl":"10.1016/j.medidd.2025.100224","url":null,"abstract":"<div><h3>Background</h3><div>Monoclonal antibodies (mAbs) are typically colorless; however, the pink coloration observed during production raises quality concerns. This study investigated the mechanism linking this color change to Vitamin B12 (VB12), which converts to hydroxycobalamin (OH-Cbl) under light and binds covalently to cysteine residues in antibodies via cobalt-sulfur bonds.</div></div><div><h3>Methods</h3><div>Three batches of IgG1 antibodies (SP1, SP2, and NL)—were expressed in CHO cells, exposed to light, and purified. Binding interactions were analyzed using HPLC, RP-UPLC/MS, SDS-PAGE, and hydrophobic interaction chromatography (HIC). Peptide mapping and 3D structural modeling using protenix and autodock vina software identified the binding sites and spatial requirements.</div></div><div><h3>Results</h3><div>OH-Cbl covalently binds to five cysteine residues: L_Csy138 and L_Csy218 (light chain) and H_Csy22, H_Csy96, and H_Csy323 (heavy chain). SP2 exhibited a higher VB12 content (molar ratio 1:5.71 vs. 1:9.74 in SP1) and increased hydrophobicity, confirming covalent attachment. Structural modeling revealed large protein pockets around these cysteines, accommodating VB12′s bulky structure. Peptide analysis revealed distinct UV absorption at 360 nm for SP2, while SDS-PAGE indicated slight molecular weight differences.</div></div><div><h3>Conclusion</h3><div>The pink coloration arises from the light-induced conversion of VB12 to OH-Cbl, which binds covalently to specific cysteine residues, facilitated by spatially permissive protein pockets. Controlling the light exposure during production can mitigate this phenomenon. This study elucidates the structural basis of antibody-VB12 interactions, offering critical insights for optimizing mAb quality control.</div></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"28 ","pages":"Article 100224"},"PeriodicalIF":0.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889619","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}
Pub Date : 2025-07-26DOI: 10.1016/j.medidd.2025.100218
Sakshi Shahapurmath, Bhuvaneshwari R. Sharannavar, Rahul Koli
Serum albumin-based nanoparticles, derived from bovine (BSA) and human (HSA) sources, have emerged as versatile carriers in drug delivery systems due to their intrinsic biocompatibility, biodegradability, and amenability to surface modification. This review provides a comprehensive analysis of recent advancements in the functionalization of albumin nanoparticles with diverse ligands to enhance targeting specificity and therapeutic efficacy. Functional moieties such as folic acid, peptides, aptamers, antibodies and their fragments, polymers, chitosan, hyaluronic acid, biotin, transferrin, cholesterol, surfactants, and apolipoproteins have been extensively explored for their role in modulating cellular uptake, drug release kinetics, and site-specific accumulation. A systematic discussion of ligand selection, conjugation strategies, and encapsulated therapeutics is presented, along with a comprehensive evaluation of in vitro and in vivo studies assessing the pharmacokinetics, biodistribution, and therapeutic potential of ligand modified albumin nanoparticles. Particular empHSAis is placed on the applications of functionalized albumin nanoparticles in oncology, inflammatory and neurological disorders, and infectious diseases. Emerging trends highlight the development of multifunctional nanocarriers integrating imaging agents for theranostic applications and the application of cutting-edge functionalization techniques to facilitate personalized medicine. This review serves as a critical resource for researchers, fostering advancements in the rational design and optimization of albumin-based nanocarriers for precision drug delivery.
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