For FBDD, MD simulations may hold some value given that fragments are small and rigid enough that transitions between binding modes may occur at shorter timescales. In this case, MD simulations could then resolve potential binding modes and reveal important stabilizing protein-ligand contacts-that is, if such contacts form on reasonable timescales (nanoseconds to milliseconds). But in some cases, binding mode transitions may require conformational changes in the protein which may take beyond the millisecond timescale before a transition can even occur. Although these challenges in adequate sampling of the biologically relevant timescales remain an issue to this day, recent advancements in the field have resulted in new ways to address sampling challenges which we apply within this study.