Replica exchange with solute tempering (REST2) is an enhanced sampling method that involves heating only a small region of the solute. Coordinates are exchanged periodically between replicas so as to allow easier crossing of energy barriers. It has been claimed that REST2 either improves free energy estimates or leaves them unchanged as compared to those obtained without REST2 (using normal MD simulations). Indeed, REST2 is supposed to allow sampling of less accessible states. However, as we have pointed out in previous studies, REST2 may lead to degradation in the accuracy of ∆∆G predictions and hence its uncritical use could be misleading. In this study, we have obtained consistent results with a statistically robust dataset of 60 randomly selected ligand pairs from our full dataset.