Low-Density Lipoproteins and Human Serum Albumin as Carriers of Squalenoylated Drugs: Insights from Molecular Simulations

Abstract

We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of docking simulations. It is shown that HSA could also act as a passive carrier of this bioconjugate. It should be noted that the binding of squalene moiety to HSA was unspecific and did not occur in the binding pockets devoted to fatty acids.

Albumin-driven disassembly of lipidic nanoparticles: the specific case of the squalene-adenosine nanodrug

“…The distribution of the binding scores for all ~20000 docking simulations is shown in Figure 8A. The strongest binding energy is -10.1 kcal/mol, while the most probable binding energy is about - It is noticeable that the binding scores for squalene-adenosine are very similar to the scores for squalene-gemcitabine obtained in previous work 40 (best score -10.8 kcal/mol and the most probable score -5.5 kcal/mol). In line with CD and SSFS observations -which have furthermore been reproduced with squalene-deoxycytidine (see SI, Figure S11 and S12) -, this suggests that interaction of different squalene bioconjugates with serum albumin mainly occurs through the squalene moiety while the drug does not play a significant role in this process and does not induce specificity to particular sites of the protein surface.…”

“…We utilized the computational model of human serum albumin (HSA) developed earlier 40 , which allowed us to reuse the representative ensemble of protein conformation extracted from extensive molecular dynamics trajectories. The statistics of obtained best docking poses suggests that SQAd binds to the vast majority of solvent-exposed amino acids of HSA in unspecific manner.…”

“…Binding of SQAd molecules to serum albumin was assessed by means of ensemble docking simulations, which account for large-scale protein dynamics. The protocol "of scanning docking" established in our previous studies 40,83,84 was used. High sequence and structural homology between HSA and BSA allowed us to use all-atom MD trajectory of pre-equilibrated HSA in water which was obtained in our previous study.…”

“…In 2010, Bildstein et al have shown that uptake of the drugs by the cells was influenced by the concentration and the nature of extracellular proteins. 29 It was later shown by radio-analysis of plasma fractions and molecular dynamic simulations that low density lipoproteins (LDL) 37 and to a lesser extent human serum albumins 37,39,40 participated in the uptake of squalene-gemcitabine bioconjugates. However, the specificity of the SQAd interactions with these biomolecules remains unknown.…”

Curvature increases permeability of the plasma membrane for ions, water and the anti-cancer drugs cisplatin and gemcitabine

“…Topologies of water and ions were taken from AMBER99sb force field. Topologies of cisplatin and gemcitabine were developed and tested in our previous works 20,25 respectively.…”