Combined in Silico and Experimental Approach for Drug Design: The Binding Mode of Peptidic and Non-Peptidic Inhibitors to Hsp90 N-Terminal Domain

Heat shock protein 90 (Hsp90) is a prime target for antitumor therapies.
The information obtained by molecular dynamics (MD) simulations is
combined with NMR data to provide a cross-validated atomic resolution
model of the complementary interactions of heat shock protein 90 with a
peptidic (shepherdin) and a non-peptidic
(5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, AICAR)
inhibitor, showing antiproliferative and proapoptotic activity in
multiple tumor cell lines. This approach highlights the relevant role of
imidazolic moiety in the interaction of both antagonist molecules. In
5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside bound state, one
conformation of those present in solution is selected, where imidazolic,
H4 and H5 protons have a key role in defining a non-polar region
contacting heat shock protein 90 surface. The dynamic equilibrium
between N-type and S-type puckered forms of
5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside moiety is shown
to be functional to inhibitor binding. The first experimental structural
data on these inhibitors are presented and discussed as hints for future
design of improved molecules.