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Optimization of the systems for active-targeting drug delivery is a pending task in view of more directed transport of the active components to neoplastic cells. One of the ways to improved performance of the drug carriers is refinement of their molecular composition, size, and specific interactions with membrane receptors. Better understanding of the latter is possible through molecular-level investigation of the process of direction of the transporters to target proteins on the surface of cells. This involves unveiling the communication between these receptors and their native ligands, which can be used as vectors for targeting the drugs. The review summarizes the current knowledge on the structure, function, and ligand binding of several most common receptors, overexpressed on various types of cancer cells, and, hence, available as potential drug delivery targets. Then, the results from molecular modeling of these proteins and ligands with atomistic equilibrium molecular dynamics simulations are recapped. The digest illustrates that the computational outcome is a valuable source of microscopic information, that accurate computational methodology is available and well mastered, and that there is much room for future developments focused on even more extensive and realistic applications in the area of targeted drug delivery.

Thorough computational description of the properties of membrane-anchored protein receptors, which are important for example in the context of active targeting drug delivery, may be achieved by models representing as close as possible the immediate environment of these macromolecules. An all-atom bilayer, including 35 different lipid types asymmetrically distributed among the two monolayers, is suggested as a model neoplastic cell membrane. One molecule of folate receptor-α (FRα) is anchored into its outer leaflet, and the behavior of the system is explored by atomistic molecular dynamics simulations. The total number of atoms in the model is ∼185 000. Three 1-μs-long simulations are carried out, where physiological conditions (310 K and 1 bar) are maintained with three different pressure scaling schemes. To evaluate the structure and the phase state of the membrane, the density profiles of the system, the average area per lipid, and the deuterium order parameter of the lipid tails are calculated. The bilayer is in liquid ordered state, and the specific arrangement varies between the three trajectories. The changes in the structure of FRα are investigated and are found time- and ensemble-dependent. The volume of the ligand binding pocket fluctuates with time, but this variation remains independent of the more global structural alterations. The latter are mostly “waving” motions of the protein, which periodically approaches and retreats from the membrane. The semi-isotropic pressure scaling perturbs the receptor most significantly, while the isotropic algorithm induces rather slow changes. Maintaining constant nonzero surface tension leads to behavior closest to the experimentally observed one.

Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems.