Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in biomolecular systems. A novel computationally effective approach (IE) was recently proposed to calculate the entropy based on the computation of protein-ligand interaction energy directly from molecular dynamics (MD) simulations. We present a study focused on the application of this method to flexible molecular systems and compare its performance with well-established normal mode (NM) and quasiharmonic (QH) entropy calculation approaches. Our results demonstrated that the IE method is intended for calculating entropy change for binding partners in fixed conformations, as by the original definition of IE, and is not applicable to the molecular complexes in which the interacting partners undergo significant conformational changes during the binding process.