Molecular dynamics simulation study and molecular docking descriptors in structure-based QSAR on acetylcholinesterase (AChE) inhibitors.

In this study we present an approach for predicting the inhibitory activity of acetylcholinesterase (AChE) inhibitors by combining molecular dynamics (MD) simulation and docking studies in a structure-based quantitative structure-activity relationship (QSAR) model. The MD simulation was performed on AChE to obtain enzyme conformation in a water environment. The resulting conformation of the enzyme was used for docking with the most potent inhibitor (26a). Docking analysis revealed that hydrophobic interactions play important roles in the AChE-inhibitor complex. Then, all inhibitors that could bind simultaneously at the catalytic site and at the peripheral anionic site of AChE were docked into the enzyme and their interactions with AChE were used as new interpretable descriptors in a structure-based QSAR model. The least squares support vector regression was constructed using the four most relevant docking descriptors and one molecular structure descriptor. The Q(2) value of the model was found to be 0.790. Furthermore, to study the enzyme conformation stability, a second MD simulation was performed on AChE-inhibitor 26a complex. In MD simulation, the topological parameters of the inhibitor were derived from the PRODRG server, and partial atomic charges were modified using the B3LYP/6-31G level of theory. The radius of gyration for the complex showed that AChE conformation did not change in the presence of the inhibitors.