Plourde Nicole M, Kortagere Sandhya, Welsh William, Moghe Prabhas V
Departments of Chemical and Biochemical Engineering and Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA.
Biomacromolecules. 2009 Jun 8;10(6):1381-91. doi: 10.1021/bm8014522.
Oxidized low density lipoprotein (oxLDL) uptake by macrophages is mediated by scavenger receptors and leads to unregulated cholesterol accumulation. Micellar nanolipoblockers (NLBs) consist of alkyl chains and polyethylene glycol on mucic acid. NLBs functionalized with anionic groups inhibit oxLDL uptake via the scavenger receptor A (SR-A). Molecular modeling and docking approaches were used to understand the structure-activity relationship (SAR) between NLBs and SR-A. Six NLB models were docked to the SR-A homology model to investigate charge placement and clustering. NLB models with the most favorable binding energy were also the most effective oxLDL inhibitors in THP-1 macrophages. Mutant SR-A models were generated by replacing charged residues with alanine. All charged residues in the region were necessary, with Lys60, Lys63, and Lys66 having the greatest effect on binding. We hypothesize that structural studies aided by theoretical modeling and docking can be used to design promising NLB candidates with optimal binding properties.
巨噬细胞对氧化型低密度脂蛋白（oxLDL）的摄取由清道夫受体介导，并导致胆固醇不受调控地积累。胶束纳米脂质阻滞剂（NLBs）由烷基链和粘酸上的聚乙二醇组成。用阴离子基团功能化的NLBs通过清道夫受体A（SR-A）抑制oxLDL的摄取。采用分子建模和对接方法来理解NLBs与SR-A之间的构效关系（SAR）。将六个NLB模型与SR-A同源模型对接，以研究电荷分布和聚集情况。结合能最有利的NLB模型也是THP-1巨噬细胞中最有效的oxLDL抑制剂。通过用丙氨酸取代带电残基生成了突变型SR-A模型。该区域中的所有带电残基都是必需的，其中Lys60、Lys63和Lys66对结合的影响最大。我们推测，借助理论建模和对接的结构研究可用于设计具有最佳结合特性的有前景的NLB候选物。
