While concentration and model-independent binding coefficients that would enable the comparison between the binding affinity of simple ions and charged small molecules to membranes are not available, we managed to evaluate the binding affinity of etidocaine and TPP to POPC lipid bilayers in MD simulations against experiments using the changes in lipid headgroup order parameters as done previously for sodium and calcium. However, the required size and length of simulations increase with increasing binding affinity, thereby setting practical limitations for the molecules that can be studied with this approach. For etidocaine and TPP, the simulation box sizes of 12-81 nm in membrane normal direction and time scales of 1-5 µs were sufficient, but the evaluation of SMS or dibucaine binding with higher affinities was not feasible within this work.