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.

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

“…By competing for SR, the NPs effectively reduce oxLDL uptake and the ensuing foam cell phenotype in hMDMs, indicating that the NPs displaying these AMs are binding with higher avidity and preventing oxLDL trafficking into macrophages. This finding is consistent with previous in silico molecular dynamics models of AMs, which indicate that the 3D structure is the strongest determinant of efficacy at inhibiting oxLDL uptake, specifically the extended conformation of the hydrophobic arms (13).…”

“…In this report, we present amphiphilic macromolecule nanoparticles (AM NPs) that have high levels of retention at atherosclerotic plaques and show progressive disease stabilization, thus exhibiting the critical design prerequisites for new lesiondirected atherosclerotic therapeutics. The modular composition of AMs allows for a wide library of features with modifications in the charge, hydrophobicity, and stereochemistry (13,26). A key aspect of this work is the design of composite nanoparticles with different shell AMs, thus generating a graded library of therapeutics.…”

“…NPs were evaluated for efficacy by measurement of oxLDL uptake inhibition, ability to bind scavenger receptors MSR1 and CD36, and ability to modulate scavenger receptor expression in hMDMs (13,18).…”

“…A parallel modeling effort was also conducted to establish a structure-activity relationship framework for predictive in silico screening and further evolution of AM candidates. Using quantitative structure-activity relationship models for each of the in vitro endpoints tested, based on previously identified 3D structures of AMs (13), molecular descriptors that highly correlated with biological activity were found (SI Appendix, Fig. S5).…”

“…Using both in vitro and in silico models, AMs were found to competitively bind macrophage SRs, thus inhibiting modified lipid internalization and foam cell formation (13)(14)(15). When complexed around hydrophobic core solutes using kinetic fabrication techniques, the AMs form nanoparticles (NPs) that display resistance to unimer release in serum-rich environments (16,17).…”