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Cyclic Peptides as Protein Kinase Inhibitors: Structure-Activity Relationship and Molecular Modeling.

Michel F Sanner1, Khalid Zoghebi2,3, Samara Hanna2

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|May 17, 2021
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Cyclic peptide [WR]9, containing arginine and tryptophan residues, is a potent inhibitor of cancer-related protein kinases. Its larger ring size enhances binding affinity and anticancer potential compared to smaller peptides.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Protein kinases are crucial in cancer cell signaling.
  • Dysregulation of protein kinases is linked to cancer development.
  • Targeting protein kinases with inhibitors is a key anticancer strategy.

Purpose of the Study:

  • To evaluate the protein kinase inhibitory potential of novel cyclic peptides.
  • To identify the structural features critical for kinase inhibition.
  • To elucidate the binding mechanism of these peptide inhibitors.

Main Methods:

  • Synthesis and evaluation of cyclic peptides ([WR]x, x=5-9) and hybrid peptides.
  • Radioactive kinase assays using [γ-33P]ATP to determine IC50 values.
  • Automated blind docking and molecular dynamics simulations to predict binding sites and mechanisms.

Main Results:

  • Cyclic peptide [WR]9 demonstrated superior inhibitory activity against c-Src, Abl, PKCa, and other kinases compared to smaller cyclic and hybrid peptides.
  • [WR]9 exhibited IC50 values as low as <0.25 μM against Akt1, Alk, and Btk.
  • Docking and simulation studies identified a non-competitive binding site near the ATP-binding pocket, with [WR]9 showing increased affinity.

Conclusions:

  • Peptide structure, specifically the presence of arginine and tryptophan residues, ring size, and amino acid count, critically influences protein kinase inhibitory potency.
  • [WR]9 is a highly potent non-competitive kinase inhibitor with significant potential as an anticancer agent.
  • The identified binding pocket and mechanism provide a rationale for [WR]9's enhanced efficacy.