title: In silico design of anti-atherogenic biomaterials.
abstract: Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties.
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, NJ 08854, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lewis
authors.forename: Vladyslav
authors.initials: V
authors.lastname: Kholodovych
authors.forename: Michael D
authors.initials: MD
authors.lastname: Tomasini
authors.forename: Dalia
authors.initials: D
authors.lastname: Abdelhamid
authors.forename: Latrisha K
authors.initials: LK
authors.lastname: Petersen
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011092:Polyethylene Glycols; D011108:Polymers / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D001672:Biocompatible Materials; D002241:Carbohydrates; D008024:Ligands; D008077:Lipoproteins, LDL; D046911:Macromolecular Substances; D011108:Polymers; C099252:oxidized low density lipoprotein; D011092:Polyethylene Glycols
keywords: Amphiphilic macromolecules; Atherosclerosis; Macrophages; Molecular modeling; Structure-activity relations
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