Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β  

木果楝亭与糖原合成酶激酶-3β结合的分子对接研究

作　　者：Christian Baillya Gérard Vergoten 

机构地区：[1]Scientific Consulting Office,OncoWitan,Wasquehal,Lille 59290,France [2]University of Lille,Inserm,INFINITE-U1286,Institut de Chimie Pharmaceutique Albert Lespagnol(ICPAL),Faculty of Pharmacy,3 rue du Professeur Laguesse,BP-83,F-59006,Lille,France

出　　处：《Digital Chinese Medicine》2022年第1期9-17,共9页数字中医药（英文）

摘　　要：Objective The mangrove tree Xylocarpus granatum J.Koenig(X.granatum)is a medicinal plant used to treat various diseases in several Asian countries.Many bioactive natural products have been isolated from the plants,particularly several groups of limonoids,including 18 xylogranatins(Xyl-A to R),all of which bear a furyl-δ-lactone core commonly found in limonoids.Based on a structural analogy with the limonoids obacunone and gedunin,we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β(GSK-3β),a major target for the treatment of neurodegenerative pathologies,viral infections,and cancers.Methods We investigated the binding of the 18 xylogranatins to GSK-3βusing molecular docking in comparison with two known reference GSK-3βATP-competitive inhibitors,LY2090314 and AR-A014418.For each compound bound to GSK-3β,the empirical energy of interaction(ΔE)was calculated and compared to that obtained with known GSK-3βinhibitors and limonoid triterpenes that target this enzyme.Results Five compounds were identified as potential GSK-3βbinders,Xyl-A,-C,-J,-N,and-O,for which the calculated empiricalΔE was equivalent to that calculated using the best reference molecule AR-A014418.The best ligand is Xyl-C,which is known to have marked anticancer properties.Binding of Xyl-C to the ATP-binding pocket of GSK-3βpositions the furyl-δ-lactone unit deep into the binding-site cavity.Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3βbinding.Structure-binding relationships are discussed.Conclusion GSK-3βmay contribute to the anticancer effects of X.granatum extract.This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3βmodulators.目的木果楝是一种红树林树木,其在多个亚洲国家作为药用植物被用于治疗多种疾病。已经从该植物中分离出许多具有生物活性的天然产物,特别是几类柠檬苦素类似物,包括18种木果楝亭(Xyl-A至R),均具有柠檬苦素类似物中常见的呋喃-δ-内酯核心。基于与柠檬苦素类似物黄柏酮和葛杜宁的结构相似性,我们假设木果楝亭可以靶向结合糖原合成酶激酶-3β(GSK-3β),该激酶是治疗神经退行性病变、病毒感染和癌症的主要靶点。方法通过分子对接技术研究18种木果楝亭与GSK-3β的结合,并与两种已知的参照物GSK-3βATP竞争性抑制剂LY2090314和AR-A014418进行比较。对于与GSK-3β结合的每种化合物,计算经验相互作用能(ΔE),并与靶向这种酶的已知GSK-3β抑制剂和柠檬苦素样三萜类获得的ΔE进行比较。结果五种化合物Xyl-A、-C、-J、-N和-O被确定为潜在的GSK-3β结合剂,其计算的ΔE相当于使用最佳参照分子ARA014418计算出的ΔE。最佳配体是Xyl-C,已知它具有显著的抗癌特性。Xyl-C与GSK-3β的ATP结合袋结合将呋喃-δ-内酯单位定位在结合位点空腔的深处。其他带有中心吡啶环或紧密多环结构的木果楝亭衍生物不太适合与GSK-3β结合。本研究同时讨论了结构绑定关系。结论GSK-3β可能有助于木果楝提取物发挥抗癌作用。本研究为鉴定其他含呋喃-δ-内酯的柠檬苦素类似物作为GSK-3β调节剂奠定了基础。

关 键 词：Natural products Xylocarpus granatum Xylogranatins Glycogen synthase kinase-3β(GSK-3β) LIMONOIDS CANCER Molecular modelling Structure-activity relationship 

分 类 号：R284[医药卫生—中药学]