How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities?: Acetylcholinesterase huprine inhibitors as a test case

This study examines the accuracy of molecular dynamics-linear response (MD/LR) and Poisson-Boltzmann/solvent accessible surface (PB/SAS) calculations to predict relative binding affinities. A series of acetylcholinesterase (AChE) huprine inhibitors has been chosen as a test system owing to the availability of free-energy (thermodynamic integration) calculations. The results obtained with the MD/LR approach point out a clear relationship between the experimental affinity and the electrostatic interaction energy alone for a subset of huprines, but the suitability of the MD/LR approach to predict the binding affinity of the whole series of compounds is limited. On the other hand, PB/SAS calculations show a marked dependence on both the computational protocol and the nature of the inhibitor-enzyme complex.