Design strategies to target crystallographic waters applied to the Hsp90 molecular chaperone

Abstract A series of novel and potent small molecule Hsp90 inhibitors was optimized using X-ray crystal structures. These compounds bind in a deep pocket of the Hsp90 enzyme that is partially comprised by residues Asn51 and Ser52. Displacement of several water molecules observed crystallographically in this pocket using rule-based strategies led to significant improvements in inhibitor potency. An optimized inhibitor (compound 17 ) exhibited potent Hsp90 inhibition in ITC, biochemical, and cell-based assays ( K d  = 1.3 nM, K i  = 15 nM, and cellular IC 50  = 0.5 μM).