Badhan Raj, Penny Jeffrey
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, UK.
Eur J Med Chem. 2006 Mar;41(3):285-95. doi: 10.1016/j.ejmech.2005.11.012. Epub 2006 Feb 21.
A three-dimensional model of human ABCB1 nucleotide-binding domain (NBD) was developed by homology modelling using the high-resolution human TAP1 transporter structure as template. Interactions between NBD and flavonoids were investigated using in silico docking studies. Ring-A of unmodified flavonoid was located within the NBD P-loop with the 5-hydroxyl group involved in hydrogen bonding with Lys1076. Ring-B was stabilised by hydrophobic stacking interactions with Tyr1044. The 3-hydroxyl group and carbonyl oxygen were extensively involved in hydrogen bonding interactions with amino acids within the NBD. Addition of prenyl, benzyl or geranyl moieties to ring-A (position-6) and hydrocarbon substituents (O-n-butyl to O-n-decyl) to ring-B (position-4) resulted in a size-dependent decrease in predicted docking energy which reflected the increased binding affinities reported in vitro.
利用高分辨率的人类TAP1转运蛋白结构作为模板，通过同源建模构建了人类ABCB1核苷酸结合结构域（NBD）的三维模型。使用计算机对接研究来探究NBD与类黄酮之间的相互作用。未修饰类黄酮的A环位于NBD的P环内，其5-羟基与Lys1076形成氢键。B环通过与Tyr1044的疏水堆积相互作用而稳定。3-羟基和羰基氧广泛参与与NBD内氨基酸的氢键相互作用。在A环（6位）上添加异戊烯基、苄基或香叶基部分，以及在B环（4位）上添加烃取代基（从正丁氧基到正癸氧基），导致预测对接能量呈尺寸依赖性降低，这反映了体外报道的结合亲和力增加。
