Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone protein that plays a vital role in maintaining the conformational integrity and stability of its client proteins . Inhibition of Hsp90 can lead to the degradation of its client proteins, many of which are important oncogenic drivers, making it an attractive target for drug discovery. The N-terminal domain of Hsp90 (N-Hsp90) binds to ATP and co-chaperones, which are essential for regulating its activity . By inhibiting the AT-Pase function of the human N-Hsp90 using ATPase inhibitors, its chaperone activity can be disrupted, which causes the client proteins to degrade and reduce tumor growth. This approach is being investigated as a potential cancer therapy, and several ATPase inhibitors have been developed for this purpose 129-131 . N-Hsp90-inhibitor complexes pose challenges for MD simulations in a variety of ways. The binding and unbinding mechanism of N-Hsp90-inhibitor complexes is complicated and dynamic, involving multiple conformational states and high flexibility of the ATP binding site . These conformational changes may occur on timescales beyond the reach of current MD simulations, making it challenging to capture the entire binding/unbinding process accurately. Moreover, such (un)binding events typically involve long timescales, and MD simulations must be run for extended periods, often on the order of microseconds or milliseconds . Additionally, modeling the interactions between inhibitors and the binding site requires considering various factors, such as polarization at the bound state, complex receptorligand binding dynamics, choice of appropriate CVs, and initial starting states. To address such challenges, dividing the conformational space of the receptor-ligand complex into a series of discrete milestones implemented in SEEKR2 and an accurate representation of the non-covalent inhibitor-receptor interactions at the binding site through the QMrebind scheme allows for accurate and efficient sampling of rare events and a greater exploration the conformational space of the receptor-ligand complex.