Paper Title
Modeling of Drug Recognition by Cyclodextrin-Based Nanostructures: A Computational Approach

Cyclodextrin (CD)-guest interactions have been extensively explored for developing supramolecular smart materials to improve solubilization, transportation and targeting of therapeutic agents. A fundamental aspect to be understood is the precise manner in which the binding process occurs. This includes the effect of the available volume in the CD cavity, the nature and size of the guest substituents, the role of solvation, and rationales for the conformational and thermodynamic characterization, both experimentally accessible. The accurate description and quantification of the interaction patterns, energetics and binding affinities of CD-guest systems by means of molecular dynamics (MD) and free-energy calculations have gained increasing interest in pharmaceutical technology and drug delivery applications. This work aims at developing a systematic modeling approach for understanding the factors that govern the formation of supramolecular nanostructures resorting to MD and potential of mean force calculations. The main topics gather different aspects in quantifying CD-guest binding. Relevant conformational aspects pertaining to variations in CD structure and type are firstly addressed, both when alone in water and upon inclusion of different guest molecules. Subsequently, competition between included small molecules and polymers in more complex formulations is discussed. The contrast between computational simulation and experimental results is also explored. Focus is also given to free-energy patterns in CD complexes, analyzing the role of non-included moieties in the stability constants, and characterizing the relevant interactions. It is seen that the effect of these parts of the guest molecule is non-trivial, and that substantial modulation of the inclusion complexes can be achieved imposing different substituents on both guest and CD molecules, with direct transposition for the modulation of properties in supramolecular structures based on these complexes. Along the same lines, the results of substituents directed at building these supramolecular structures are inspected following a DoE inspired approach. Finally, the role of the volume and flexibility of the CD host in inclusion complexes involving different model drugs is evaluated, for providing a general picture of the recognition behavior. The effect of different imposed features on the stability of inclusion complexes between CD and several guests is thus investigated in terms of structural, mechanistic and thermodynamic aspects. Complexation of the model guests is sensitive to alterations in the basic backbone and in the available cavity volume, as the fit variations into the host cavity have a direct impact on the respective binding constants. These have direct implication in guest encapsulation and release from CD molecules and include substitution, size, conformation, orientation, flexibility, fit and contact, solvation, and energy. Keywords - Cyclodextrins; Supramolecular structures; Inclusion complexes; Host-guest interactions; Molecular simulation; Drug delivery