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

SUBMITTER: Tomaselli S 

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

REPOSITORIES: biostudies-literature