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

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.