| Abstract [eng] |
Chaperone Hsp90, being essential to the main cancerogenesis pathways, is an attractive target for development of anticancer drugs. A series of potential Hsp90 inhibitors, aryl-dihydroxyphenyl-thiadiazoles, has been synthesised at Vilnius University. The goal of this study was to explore the structure-thermodynamics relationship for aryl-dihydroxyphenyl-thiadiazoles to human Hsp90. We employed isothermal titration calorimetry in conjunction with protein denaturation profile analysis techniques in order to dissect the thermodynamic mechanism of the protein–ligand binding event. In this work we provide a detailed thermodynamic characterisation of these inhibitors binding to recombinant human Hsp90, both α and β isoforms. We show for the first time that protonation of hydroxyl residue in resorcinol-based Hsp90 inhibitors is essential for binding. Comparison of thermodynamic and structural data signified the ability of chlorine to form interactions of non-hydrophobic nature. As generally enthalpic contribution to the ligand affinity is more difficult to improve than the entropic contribution, the mostly enthalpy-driven binding of three of our compounds makes them excellent candidates for further lead development. |
