Molecular Modeling to Study Dendrimers for Biomedical Applications

Abstract

Molecular modeling techniques provide a powerful tool to study the properties of molecules and their interactions at the molecular level. The use of computational techniques to predict interaction patterns and molecular properties can inform the design of drug delivery systems and therapeutic agents. Dendrimers are hyperbranched macromolecular structures that comprise repetitive building blocks and have defined architecture and functionality. Their unique structural features can be exploited to design novel carriers for both therapeutic and diagnostic agents. Many studies have been performed to iteratively optimise the properties of dendrimers in solution as well as their interaction with drugs, nucleic acids, proteins and lipid membranes. Key features including dendrimer size and surface have been revealed that can be modified to increase their performance as drug carriers. Computational studies have supported experimental work by providing valuable insights about dendrimer structure and possible molecular interactions at the molecular level. The progress in computational simulation techniques and models provides a basis to improve our ability to better predict and understand the biological activities and interactions of dendrimers. This review will focus on the use of molecular modeling tools for the study and design of dendrimers, with particular emphasis on the efforts that have been made to improve the efficacy of this class of molecules in biomedical applications.

Figure 1

Structural properties of dendrimers; (A) Divergent synthesis; (B) Convergent synthesis; (C) Different topological structures that can be obtained from synthesis.

Figure 2

Topological structures obtained with different core and branching monomers; From top to bottom: monomeric units, 2D structure of a G2 dendrimer, 3D structure of G2 dendrimer.

Figure 3

Biomedical applications where MD has been important to probe biological interactions.

Figure 4

Example of the dotted cap notation for a poly(aspartic acid) dendrimer; The dendrimer is represented by the core, branches and capping groups; This type of notation is useful since several capping groups with different branching points can be easily compared.

Figure 5

Strategy employed for building dendrimers of different types and generations using XPLOR [71].

Figure 6

Docking strategies applied to dendrimer studies. Depending on the size either the dendrimer or the biomolecule can be described as the docking center. The docking site can be defined either in a small space of the dendrimer or in the whole structure (middle figures). The generated docking structures can then be submitted to MD simulations or the conformations from MD simulations can be used to dock the molecules (Bottom figures).

Figure 7

Availability of the substituted terminal glucosamine groups on PAMAMs’ surface. Reprinted from [90].

Figure 8

Proposed mechanism for high generation of PAMAM dendrimers; there is an initial attraction to the membrane governed by several forces (e.g., electrostatic); once the dendrimer is near the membrane the inner leaflet promotes interactions with the dendrimer. For high generation, the dendrimer is not able to flat and causes perturbation on the membrane leading to the formation of a vesicle encasing the dendrimers with subsequent formation of a pore.

Figure 9

PAMAM dendrimers’ hydrophilic surface (blue) and hydrophobic core (orange). Adapted from [45].

Figure 10

Docking between Dendrimer glucosamine and MD-2 protein and inhibition of TLR4-MD-2-LPS complex formation; adapted from [52].