分子对接分析地高辛衍生物选择性拮抗RORγt活性  

Investigation of selective inhibition of digoxin derivative on retinoic acid-related orphan nuclear receptor γt transcription activity using molecular docking

作　　者：钟彩梅[1] 蔡译萱[1] 王美容[1] 郑秀芬[2] 邱贤文[1] 孙乐栋[1] 张帆[1] 张堂德[1] 

机构地区：[1]南方医科大学珠江医院皮肤病与性病科,广东广州510282 [2]南方医科大学附属顺德第一人民医院皮肤科,广东顺德528000

出　　处：《南方医科大学学报》2014年第4期511-518,共8页Journal of Southern Medical University

基　　金：广东省医学科学技术研究基金(B2012240)

摘　　要：目的银屑病是一种慢性炎症性免疫性疾病,与Th17细胞的功能失调密切相关。RORγt影响Th17细胞的分化、成熟;并在该细胞所致的免疫紊乱中发挥极为重要的作用。本文主要探讨地高辛衍生物选择性拮抗RORγt转录活性的潜在机制。方法地高辛为对照,通过分子对接的方法结合分子间的静电势能(MEP)分析地高辛衍生物(Dhd)与RORs(RORα,RORβ和RORγt)的相互作用;通过荧光素酶报告基因系统进一步验证分子对接结果。结果分子对接结果示Dhd仅影响RORγt分子构象;荧光素酶报告基因检测示Dhd选择性拮抗RORγt转录活性,该拮抗作用可呈时-效性和量-效性。结论 Dhd选择性拮抗RORγt转录活性。Objetive Psoriasis is an autoimmune-related chronic inflammatory skin disease strongly associated with the dysfunction of Th17 cells. Retinoic acid-related orphan nuclear receptor γt （RORγt） plays a critical role in the differentiation and maturation of Th17 ceils and in cell-derived immunologic derangement. We conducted this study to investigate potential mechanism by which the derivative of digoxin selectively antagonizes RORyt transcriptional activity. Method Using molecular docking in combination with molecular electrostatic potential （MEP）, we detected the interaction between the derivative of digoxin （Dhd） and ROR transcription factor （RORa, RORβ and RORγt）, and the results were further confirmed by bioluminescent assay. Result Molecular docking demonstrated that Dhd could exclusively inhibit the conformation of RORyt; bioluminescent assay further indicated that RORyt was selectively antagonized by Dhd in a dose and time-dependent manner. Conclusion Dhd can selectively suppress RORyt transcriptional activity.

关 键 词：RORΓT 分子对接 地高辛 免疫性疾病 

分 类 号：R758.63[医药卫生—皮肤病学与性病学]