As an attractive anticancer target, the Hsp90 chaperone machine regulates a wide range of oncoproteins. Most of the Hsp90 inhibitors in clinical trials employ the same ATP blockage mechanism while little progress has been achieved with Hsp90-cochaperone complexes. Numerous protein kinases associate with the Hsp90-Cdc37 PPI, a potential target for the treatment of cancers, to implement folding and maturation. In order to explore the key residues of the Hsp90-Cdc37 binding interface for further design of peptide inhibitors, a combined strategy of molecular dynamics simulation and MM-PBSA analysis was performed. Subsequent design and identification of an eleven-residue peptide (Pep-1) directly derived from the Cdc37 binding interface was achieved to exhibit a 6.9 μM binding capacity and 3.0 μM ATPase inhibitory rate. This is the first evidence that a peptide inhibitor not only interferes with Hsp90 ATPase ability but also disrupts the Cdc37-Hsp90 PPI.
|Original language||English (US)|
|Number of pages||8|
|State||Published - Oct 28 2015|
ASJC Scopus subject areas
- Chemical Engineering(all)