Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors

Residence
time and more recently the association rate constant kon are increasingly acknowledged as important parameters
for in vivo efficacy
and safety of drugs. However, their broader consideration in drug
development is limited by a lack of knowledge of how to optimize these
parameters. In this study on a set of 176 heat shock protein 90 inhibitors,
structure–kinetic relationships, X-ray crystallography, and
molecular dynamics simulations were combined to retrieve a concrete
scheme of how to rationally slow down on-rates. We discovered that
an increased ligand desolvation barrier by introducing polar substituents
resulted in a significant kon decrease.
The slowdown was accomplished by introducing polar moieties to those
parts of the ligand that point toward a hydrophobic cavity. We validated
this scheme by increasing polarity of three Hsp90 inhibitors and observed
a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation
in residence time. This prolongation was driven by transition state
destabilization rather than ground state stabilization.