title: Structure-activity relations of nanolipoblockers with the atherogenic domain of human macrophage scavenger receptor A.
abstract: 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.
authors.affiliation: Departments of Chemical and Biochemical Engineering and Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Plourde
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.forename: William
authors.initials: W
authors.lastname: Welsh
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism*; D002460:Cell Line; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D053758:Nanoparticles; D051117:Scavenger Receptors, Class A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A