Combined in silico and experimental approach for drug design: the binding mode of peptidic and non-peptidic inhibitors to hsp90 N-terminal domain.

ABSTRACT: 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-β-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-β-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-β-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.

SUBMITTER: Tomaselli S 

PROVIDER: S-EPMC2953720 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature