Exploiting Conformational Dynamics in Drug Discovery: Design of C-Terminal Inhibitors of Hsp90 with Improved Activities

The interaction that occurs between molecules is a dynamic process that
impacts both structural and conformational properties of the ligand and
the ligand binding site. Herein, we investigate the dynamic cross-talk
between a protein and the ligand as a source for new opportunities in
ligand design. Analysis of the formation/disappearance of protein
pockets produced in response to a first-generation inhibitor assisted in
the identification of functional groups that could be introduced onto
scaffolds to facilitate optimal binding, which allowed for increased
binding with previously uncharacterized regions. MD simulations were
used to elucidate primary changes that occur in the Hsp90 C-terminal
binding pocket in the presence of first-generation ligands. This data
was then used to design ligands that adapt to these receptor
conformations, which provides access to an energy landscape that is not
visible in a static model. The newly synthesized compounds demonstrated
antiproliferative activity at similar to 150 nM concentration. The
method identified herein may be used to design chemical probes that
provide additional information on structural variations of Hsp90
C-terminal binding site.