{"title":"去甲苏氨酸类单体生物碱和二聚生物碱与α-微管蛋白的相互作用:分子对接研究","authors":"Gérard Vergoten, Christian Bailly","doi":"10.37349/eds.2024.00047","DOIUrl":null,"url":null,"abstract":"Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"131 38","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study\",\"authors\":\"Gérard Vergoten, Christian Bailly\",\"doi\":\"10.37349/eds.2024.00047\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.\",\"PeriodicalId\":72998,\"journal\":{\"name\":\"Exploration of drug science\",\"volume\":\"131 38\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-05-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Exploration of drug science\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.37349/eds.2024.00047\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Exploration of drug science","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.37349/eds.2024.00047","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1
摘要
目的:改善癌症治疗需要新的微管靶向药物。最近,抗癌生物碱 securinine 作为一种微管蛋白结合剂的表征促使我们探索相关单体和二聚体类似物与微管蛋白的相互作用。我们采用分子对接法研究了α/β-微管蛋白二聚体与从灌木 Flueggea virosa (Roxb. ex Willd.) Royle 中分离出来的生物碱 fluevirines A-F 和 flueggenines A-I 之间的相互作用。研究方法首先比较了两种securinine与α/β-tubulin结合的分子模型。在随后与所有化合物的对接分析中,选择了 pironetin 结合位点模型(5FNV)。测量并比较了相互作用的经验能量(ΔE)。结果Fluevirine A 被鉴定为一种强效的小管蛋白粘合剂。这种二聚生物碱与小管蛋白形成的复合物比单体化合物(如氟韦林 B-D)更稳定。双吲哚衍生物氟病毒因子 E 也能提供比 (nor)securinine 更稳定的复合物。研究扩展到了二聚生物碱氟矢车菊碱 A-I,并确定了三种化合物为潜在的小管蛋白结合剂:多环产物氟矢车菊碱 B、去甲琥珀酰-吲哚杂化物氟矢车菊碱 E 和去甲琥珀酰二聚物氟矢车菊碱 I。后一种化合物被证明能很好地适应微管蛋白的 pironetin 位点,在秋水仙碱结合区和 pironetin 位点之间延伸出两个去甲苏氨酸单元,非常靠近 pironetin 反应半胱氨酸-316 残基。对结构-结合关系进行了描述。结论:这项研究确定了二聚生物碱氟卫宁 A 和氟卫宁 I 是潜在的 α-管蛋白结合剂。这是首次将包括两个 C-C 连接的去甲嘌呤单位的二聚生物碱鉴定为微管蛋白配体。这项研究有助于人们更好地了解 Flueggea 生物碱的作用机制,并有助于设计以 α-微管蛋白的 pironetin 位点为靶点的抗癌类似物。
Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study
Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.