Combined MD/QTAIM techniques to evaluate ligand-receptor interactions. Scope and limitations.

In medicinal chemistry, it is extremely important to evaluate, as accurately as possible, the molecular interactions involved in the formation of different ligand-receptor (L-R) complexes. Evaluating the different molecular interactions by quantum mechanics calculations is not a simple task, since formation of an L-R complex is a dynamic process. In this case, the use of combined techniques of molecular dynamics (MD) and quantum calculations is one the best possible approaches. In this work we report a comparative study using combined MD and QTAIM (Quantum Theory of Atoms In Molecules) calculations for five biological systems with different levels of structural complexity. We have studied Acetylcholinesterase (AChE), D2 Dopamine Receptor (D2DR), beta Secretase (BACE1), Dihydrofolate Reductase (DHFR) and Sphingosine Kinase 1 (SphK1). In these molecular targets, we have analyzed different ligands with diverse structural characteristics. The inhibitory activities of most of them have been previously measured in our laboratory. Our results indicate that QTAIM calculations can be extremely useful for in silico studies. It is possible to obtain very accurate information about the strength of the molecular interactions that stabilize the formation of the different L-R complexes. Better correlations can be obtained between theoretical and experimental data by using QTAIM calculations, allowing us to discriminate among ligands with similar affinities. QTAIM analysis gives fairly accurate information for weak interactions which are not well described by MD simulations. QTAIM study also allowed us to evaluate and determine which parts of the ligand need to be modified in order to increase its interactions with the molecular target. In this study we have discussed the importance of combined MD/QTAIM calculations for this type of simulations, showing their scopes and limitations.