Characterization of the conformational ensemble from bioactive N-acylhydrazone derivatives

The search for bioactive conformations from prototypes is mostly referenced on crystallographic ligand-receptor complexes, in which the molecule conformation is already caged inside its binding site. However, the complexation process is a thermodynamic event depending on both complexed and uncomplexed states. As ligand affinity originates from such equilibrium, the development of novel computational models capable of supplying data on ligand dynamics in biological solutions is potentially applicable in more efficient methods for prediction of compounds binding and affinity. In this context, the current work employs a series of molecular dynamics simulations on three N-acylhydrazone derivatives, already shown to present promising cardioinotropic and vasodilatory activities, in order to obtain a precise characterization of each compound conformational ensemble in aqueous solutions, instead of a single minimum energy conformation. Consequently, we were able to observe the influence of each functional group of the studied molecules on the conformation of the entire compounds and thus on the exposure of functional groups that might potentially bind to target receptors. Additionally, the differences between the molecules conformational behavior were characterized, supporting a spatial and temporal image of each ligand, which may be potentially correlated to their biological activities. So in the context of conformational selection, such strategy may represent a useful methodology to contribute in the choice of ligands conformations for both 3D-QSAR and docking calculations.