τ-random acceleration molecular dynamics (τRAMD) is an enhanced sampling computational approach for exploring relevant biomolecular pathways and ranking drug candidates by estimated mean first passage times (MFPT) . Recently, τRAMD has been used to observe the ligand unbinding pathway for a series of 70 N-Hsp90 inhibitors and ranked them according to their rel- ative residence times. N-Hsp90 protein has been shown to acquire different conformations, namely the loop and the helix conformations . In the loop conformation, inhibitors bind solely to the ATP binding site, while in the helix conformation, inhibitors additionally occupy a hydrophobic transient subpocket situated between α-helix3 and the beta-strands, thereby stabilizing the α-helix3 domain (Figure ). This study chooses a subset of 17 inhibitors representing significant diversity in molecu-lar scaffold among 70 inhibitors (Table ). inhibitors possess varying residence times within the protein, bind to either the loop or the helix conformation of the protein, and are classified into different groups, including resorcinol, hydroxy-indazole, benzamide, aminoquinazoline, aminopyrrolopyrimidine, and 2aminopyramidine, based on their structural diversity, scaffold, and chemical motifs (Figure ). Absolute unbinding kinetics (k off ) for eight of the 17 are calculated using the original force field parameters input directly into SEEKR2 and the QMrebind+SEEKR2 approach and are compared against the experimental values. PDB and topology files for the Hsp90-inhibitor complexes are obtained from the original study 137 . In the same study, the ligands were parameterized using the Antechamber program, and electrostatic potentials derived from ab initio calculations were employed to fit the restrained electrostatic potential (RESP) atomic partial charges at the HF level with a 6-31G*(1d) basis set. While the general Amber force field (GAFF) was applied to the ligands for all non-charge parameters, the protein was parameterized with the Amber14 force field .