Overall, we showed that microsecond MD simulations of small fragment-like molecules in the large SEH binding site were unable to adequately sample ligand binding mode transitions, even within a given sub-cavity, which resulted in MD failing to produce correct populations. Only by accelerating the sampling using random ligand rotations via our BLUES approach were we able to recover binding mode populations which correctly identified crystallographic binding modes in most cases. While MD did do better than docking at discovering crystallographic binding modes, even with the relatively long MD simulation time, we found most MD simulations remained trapped in or near a binding mode other than the crystallographic binding mode and, often, relatively near the starting dock pose. Since these simulations often remained trapped, our conclusion is that the best general approach is to use a variety of starting poses from docking to get good coverage of the binding site and run simulations to refine the pose such that it can recover likely potential binding modes, including potentially the crystallographic binding mode.