Abstract:
:Targeting Hsp90-Cdc37 protein-protein interaction (PPI) is becoming an alternative approach for future anti-cancer drug development. We previously reported the discovery of an eleven-residue peptide (Pep-1) with micromolar activity for the disruption of Hsp90-Cdc37 PPI. Efforts to improve upon the Pep-1 led to the discovery of more potent modulators for Hsp90-Cdc37 PPI. Through the analysis of peptides binding patterns, more peptides were designed for further verification which resulted in Pep-5, the shortest peptide targeting Hsp90-Cdc37, exerting the optimal structure and the most efficient binding mode. Subsequent MD simulation analysis also confirmed that Pep-5 could perform more stable binding ability and better ligand properties than Pep-1. Under the premise of retentive binding capacity, Pep-5 exhibited lower molecular weight and higher ligand efficiency with a Kd value of 5.99μM (Pep-1 Kd=6.90μM) in both direct binding determination and biological evaluation. The optimal and shortest Pep-5 might provide a breakthrough and a better model for the future design of small molecule inhibitors targeting Hsp90-Cdc37 PPI.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Wang L,Li L,Fu WT,Jiang ZY,You QD,Xu XLdoi
10.1016/j.bmc.2016.10.028subject
Has Abstractpub_date
2017-01-01 00:00:00pages
233-240issue
1eissn
0968-0896issn
1464-3391pii
S0968-0896(16)30920-8journal_volume
25pub_type
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