pH is an important physicochemical property that modulates proteins' structure and interaction patterns. A simple change in a site's protonation state in an enzyme's catalytic pocket can strongly alter its activity and its affinity to substrate, products, or inhibitors. We addressed this pH effect issue by evaluating its impact on donepezil binding to acetylcholinesterase (AChE). We compared the binding affinities obtained from molecular docking (weighted from the protonation states sampled by constant-pH MD) with those from molecular mechanics/Poisson-Boltzmann surface area and isothermal titration calorimetry data. The computational methods showed a clear trend where donepezil binding to the catalytic cavity is improved with the drug protonation (lowering pH). However, the loss of binding affinity observed experimentally at pH 6.0 indicates that other phenomena eluding our computational approaches are occurring. Possible factors include the shape of the access tunnel to the AChE catalytic pocket (which is captured in our MD time scale) or an entropic penalty difference between neutral and protonated donepezil. Altogether, this work highlighted the need to improve our computational methods to capture the pH effects in protein/drug binding, while also exposing the limitations that will inevitably arise from these new advances.