A low k off denotes an extended residence time for the ligand, characterizing it as a high-affinity binder (as observed for ligand 1). Conversely, ligand 9 exhibits a relatively higher k off as compared to ligand 1, indicating rapid dissociation from the binding site, classifying it as a low-affinity binder. To explain the variations in residence times, we computed the distances between the center of mass (COM) of the ligands and the COM of α-carbon atoms of the binding site residues for both the Hsp90-ligand 1 and Hsp90-ligand 9 complexes, as depicted in Figure and 10b. Changes in the ligand-binding site COM-COM distance during the simulation may suggest shifts in the interaction dynamics between the ligand and the receptor protein. In the context of the Hsp90-ligand 1 complex, a notable decrease in the COM-COM distance is evident at approximately 6 µs into the simulation, suggesting a modification in its interaction pattern with the binding site residues, as illustrated in Figure . This dynamic behavior could potentially contribute to an increased receptor-ligand interaction or efficient binding, contributing to a smaller k off .