Effective binding energies were computed over one MD trajectory that resulted in binding of 5b in the CTD dimerization interface and led to a binding mode in which 5b mimics H5'. In the computations, the single trajectory approach was used, where complex, protein, and ligand configurations were extracted from the complex trajectory. After removing water molecules and counterions, gas-phase energies (van der Waals and electrostatic contributions) were evaluated on every frame sampled at an interval of 200 ps using MMPBSA.py ; the polar contribution to the solvation free energy was calculated using the "OBC II" generalized Born model , together with mbondi2 radii and a dielectric constant of 1 for the solute and 80 for the solvent. The ionic strength was set to 150 mM of a 1:1 salt. The non-polar contribution to the solvation free energy was calculated as a function of the solvent-accessible surface area using 0.0050 kcal mol -1 Å -2 as surface tension. No absolute binding free energies can be derived from this approach since configurational entropy contributions are not considered here to reduce the uncertainty in the computations. . However, the sum of gas-phase energies and solvation free energies, the effective energy, is suitable to estimate relative differences in binding free energies for differential binding poses. WB & Blue-native gels: Cells were treated with the indicated concentration of the compound or vehicle (DMSO) for 48 hours. Immunoblot analysis was performed by following standard protocol using antibodies: anti-Hsp90 (#4877), anti-Hsp70 (#4872), anti-Hsp40 (#4871), anti-Hsp27 (#2402), anti-HSF-1 (#4356), anti-Hsp60 (#12165), anti-PDI (#2446), anti-Hsp90α (#8165), anti-Hsp90β (#5087), anti-c-Abl (#2862), anti-phospho-c-Abl (#2865), anti-Stat5 (#9363), anti-phospho-Stat5 (#9351), anti-CrkL (#3182), anti-phospho-Crkl (#3181), anti-Akt (#2920), anti-phospho-Akt (#4060) , anti-S6 ribosomal protein (#2217), anti-phospho-S6 ribosomal protein (#4858), anti-c-Myc (#13987) from Cell Signaling Technology and anti-β-actin (Sigma-Aldrich). Blue-native (BN) gels were performed following manufacturer's instructions (Invitrogen) and performed previously. Briefly, lysates were generated from K562 cell line after 48 h treatment with inhibitors (at indicated concentration) using NativePAGE Sample Prep kit (Invitrogen) by 2-3 freezing thawing cycles followed by centrifugation at 20,000 x g for 25-30 min at 4°C. Dimerization assay: Hsp90 CTD dimerization was evaluated using an amine-reactive chemical crosslinker bis(sulfosuccinimidyl) suberate (BS 3 ) (Pierce). Hsp90α CTD protein (2 µM) was diluted in the concentration of IM (Sigma-Aldrich, St. Louis, MO, USA) over a period of 3 months. Bortezomib (BTZ) resistant clones (80 nM) of HL60 (HL60-BTZr) was established following similar protocol as described to pick IM resistant clones. Primary patient derived CML CD34+ blast cells were cultured in mononuclear cell medium (PromoCell, Heidelberg, Germany).