Optimization and bioevaluation of Cdc37-derived peptides: An insight into Hsp90-Cdc37 protein-protein interaction modulators.
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 Kdvalue 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.
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Lei
L
Wang
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Li
L
Li
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China.
Wei-Tao
WT
Fu
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Zheng-Yu
ZY
Jiang
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
Qi-Dong
QD
You
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xiaoli_xu@126.com.
Xiao-Li
XL
Xu
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry*; D018833:Chaperonins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D009842:Oligopeptides; D018833:Chaperonins
Hot-spots; Hsp90-Cdc37 PPI; MD simulation; Peptides; Protein-protein interaction