Ligand selection from the analysis of protein conformational substates: new leads targeting the N-terminal domain of Hsp90

The dynamic properties of proteins underlie every aspect of their
functions in the cell. The atomistic description of protein motions and
their inclusion in ligand selection processes may provide new
opportunities for hit identification and drug discovery. Herein, we
present a novel rational strategy that allowed us to computationally
select new N-terminal targeted inhibitors of the molecular chaperone
Hsp90 starting from the atomistic analysis of the conformational
dynamics of the complex between the protein and its natural ligand ATP.
First of all, we have identified the relevant representatives of
distinct conformational substates of the Hsp90-ATP complex through the
application of a novel structural clustering strategy and, for each of
them, we have afterwards characterized the nucleotide-protein
interactions to build a pharmacophore model recapitulating the binding
hotspots conserved in different ensembles of protein conformations. The
resulting pharmacophore has been finally used to screen a database of
small molecules and allowed us to identify novel drug-like molecules
with interesting activities against Hsp90 functions in experimental
models of cancer cells. The results and the experimental validation of
the selected molecules provide support for the feasibility of including
protein flexibility in drug selection strategies through the
characterization of relevant substates.