The second compound has a cage with four naphtalene sidewalls whose flipping defines several different, slowly inter-converting conformations that can be distinguished in NMR spectra. In the present paper, at fixed CPU/simulation time allocation, we compare the efficiency of HREM and standard MD simulations in these conformationally challenging host molecules. In particular, the sampling effectiveness of standard MD simulations, at constant CPU investment time, is tested using i) a single long trajectory and ii) replicates of independent short trajectories. For the HREM simulations, we compare, at constant replica number and constant CPU time, the performance of an on-the-fly iterative scheme for acceptance ratio equalization with a commonly adopted stationary scaling protocol Convergence of vanilla MD, MD replicates and HREM with and without acceptance ratio equalization have been further assessed and compared in a biologically relevant system, consisting in the complex of a 3-(trifluoromethyl)phenyl]-5-isoxazolamine compound (ORD) with the first bromodomain-containing protein 4 (BRD4). Such peculiar system is characterized by two distinct ligand poses, whose probability ratio is strongly affected by the alchemical state of the ligand.