{"title":"靶向人极光激酶C的新型抗癌药物的探索","authors":"Deepali Gupta, Prakash Kumar Shukla, Subarnarekha Chowdhury, Supriya Kumari, Punit Kaur, Mukesh Kumar","doi":"10.1002/jcb.70025","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Aurora kinases (AKs), a family of serine/threonine kinases, play a vital role in chromosome segregation during the cell cycle (Mountzios et al., 2008). This family includes Aurora Kinase A (AKA), Aurora Kinase B (AKB), and Aurora Kinase C (AKC). AKA and AKB are active during mitosis, while AKC is involved mostly in germ cell as well as somatic cells. Elevated levels of AKC have been found in several cancer cell lines including breast, cervical, thyroid, colorectal, and liver cancers, making it a significant target for cancer therapy (Tang et al., 2017). In cancers such as glioblastoma and prostate cancer, for example, AKC up regulation has been associated with increased tumor aggressiveness, highlighting its potential role in tumor progression and poor prognosis. Our study employs computational methods, including molecular docking and structure-based virtual screening, to explore a data set of 2 65 241 compounds from the National Cancer Institute (NCI) database, focusing on AKC as a potential target for drug discovery. Through docking studies, several promising compounds that interact with the enzyme's ATP binding pocket, particularly with residues Phe54, Lys72, Ala123, Glu121 and Glu127 of AKC, were identified. The stability of these interactions was assessed through 200-ns molecular dynamics (MD) simulations, revealing that the majority of compounds exhibited stable interactions, while a few displayed fluctuations in their trajectories. Most compounds adhered to favorable pharmacokinetic properties. Comprehensive MD simulations and free energy calculations identified three top candidates (90 729, 37 623, and 134 546) with strong potential as potent inhibitors of AKC. Additional in vitro and in vivo studies are required to confirm the therapeutic potential of these candidates.</p></div>","PeriodicalId":15219,"journal":{"name":"Journal of cellular biochemistry","volume":"126 3","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"“Exploration of Novel Anticancerous Agents Targeting Human Aurora Kinase C”\",\"authors\":\"Deepali Gupta, Prakash Kumar Shukla, Subarnarekha Chowdhury, Supriya Kumari, Punit Kaur, Mukesh Kumar\",\"doi\":\"10.1002/jcb.70025\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>Aurora kinases (AKs), a family of serine/threonine kinases, play a vital role in chromosome segregation during the cell cycle (Mountzios et al., 2008). This family includes Aurora Kinase A (AKA), Aurora Kinase B (AKB), and Aurora Kinase C (AKC). AKA and AKB are active during mitosis, while AKC is involved mostly in germ cell as well as somatic cells. Elevated levels of AKC have been found in several cancer cell lines including breast, cervical, thyroid, colorectal, and liver cancers, making it a significant target for cancer therapy (Tang et al., 2017). In cancers such as glioblastoma and prostate cancer, for example, AKC up regulation has been associated with increased tumor aggressiveness, highlighting its potential role in tumor progression and poor prognosis. Our study employs computational methods, including molecular docking and structure-based virtual screening, to explore a data set of 2 65 241 compounds from the National Cancer Institute (NCI) database, focusing on AKC as a potential target for drug discovery. Through docking studies, several promising compounds that interact with the enzyme's ATP binding pocket, particularly with residues Phe54, Lys72, Ala123, Glu121 and Glu127 of AKC, were identified. The stability of these interactions was assessed through 200-ns molecular dynamics (MD) simulations, revealing that the majority of compounds exhibited stable interactions, while a few displayed fluctuations in their trajectories. Most compounds adhered to favorable pharmacokinetic properties. Comprehensive MD simulations and free energy calculations identified three top candidates (90 729, 37 623, and 134 546) with strong potential as potent inhibitors of AKC. 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引用次数: 0
摘要
Aurora激酶(AKs)是一个丝氨酸/苏氨酸激酶家族,在细胞周期的染色体分离中起着至关重要的作用(Mountzios et al., 2008)。该家族包括极光激酶A (AKA),极光激酶B (AKB)和极光激酶C (AKC)。AKA和AKB在有丝分裂过程中活跃,而AKC主要参与生殖细胞和体细胞。在乳腺癌、宫颈癌、甲状腺癌、结直肠癌和肝癌等多种癌细胞系中发现AKC水平升高,使其成为癌症治疗的重要靶点(Tang et al., 2017)。例如,在胶质母细胞瘤和前列腺癌等癌症中,AKC上调与肿瘤侵袭性增加有关,突出了其在肿瘤进展和不良预后中的潜在作用。我们的研究采用计算方法,包括分子对接和基于结构的虚拟筛选,探索来自国家癌症研究所(NCI)数据库的265241种化合物的数据集,重点关注AKC作为药物发现的潜在靶点。通过对接研究,发现了几种与酶的ATP结合袋相互作用的有希望的化合物,特别是与AKC的Phe54, Lys72, Ala123, Glu121和Glu127残基相互作用。通过200-ns分子动力学(MD)模拟评估了这些相互作用的稳定性,揭示了大多数化合物表现出稳定的相互作用,而少数化合物表现出其轨迹的波动。大多数化合物具有良好的药代动力学性质。综合MD模拟和自由能计算确定了三种最有潜力的候选药物(90 729、37 623和134 546)作为AKC的有效抑制剂。需要更多的体外和体内研究来证实这些候选药物的治疗潜力。
“Exploration of Novel Anticancerous Agents Targeting Human Aurora Kinase C”
Aurora kinases (AKs), a family of serine/threonine kinases, play a vital role in chromosome segregation during the cell cycle (Mountzios et al., 2008). This family includes Aurora Kinase A (AKA), Aurora Kinase B (AKB), and Aurora Kinase C (AKC). AKA and AKB are active during mitosis, while AKC is involved mostly in germ cell as well as somatic cells. Elevated levels of AKC have been found in several cancer cell lines including breast, cervical, thyroid, colorectal, and liver cancers, making it a significant target for cancer therapy (Tang et al., 2017). In cancers such as glioblastoma and prostate cancer, for example, AKC up regulation has been associated with increased tumor aggressiveness, highlighting its potential role in tumor progression and poor prognosis. Our study employs computational methods, including molecular docking and structure-based virtual screening, to explore a data set of 2 65 241 compounds from the National Cancer Institute (NCI) database, focusing on AKC as a potential target for drug discovery. Through docking studies, several promising compounds that interact with the enzyme's ATP binding pocket, particularly with residues Phe54, Lys72, Ala123, Glu121 and Glu127 of AKC, were identified. The stability of these interactions was assessed through 200-ns molecular dynamics (MD) simulations, revealing that the majority of compounds exhibited stable interactions, while a few displayed fluctuations in their trajectories. Most compounds adhered to favorable pharmacokinetic properties. Comprehensive MD simulations and free energy calculations identified three top candidates (90 729, 37 623, and 134 546) with strong potential as potent inhibitors of AKC. Additional in vitro and in vivo studies are required to confirm the therapeutic potential of these candidates.
期刊介绍:
The Journal of Cellular Biochemistry publishes descriptions of original research in which complex cellular, pathogenic, clinical, or animal model systems are studied by biochemical, molecular, genetic, epigenetic or quantitative ultrastructural approaches. Submission of papers reporting genomic, proteomic, bioinformatics and systems biology approaches to identify and characterize parameters of biological control in a cellular context are encouraged. The areas covered include, but are not restricted to, conditions, agents, regulatory networks, or differentiation states that influence structure, cell cycle & growth control, structure-function relationships.