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In Silico Design of MDM2‐Targeting Peptides from a Naturally Occurring Constrained Peptide
Author(s) -
Ma He,
Qiu Peiju,
Harvey Peta J.,
Li Xiao,
Zhang Zheyu,
Xu Qingliang,
Liang Jiazhen,
Kaas Quentin,
Craik David J.,
Yang Jinbo,
Jiang Tao,
Bi Xiaolin,
Yu Rilei
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900366
Subject(s) - in silico , peptide , epitope , mutant , chemistry , binding site , biochemistry , peptide sequence , biology , computational biology , antibody , genetics , gene
Naturally occurring constrained peptides are frequently used as scaffolds for bioactive peptide grating due to their high stability. Here, we used in silico methods to design several constrained peptides comprising a scorpion toxin scaffold, a MDM2 binding epitope, and a cluster of positively charged residues. The designed peptides displayed varied binding affinity to MDM2 despite differing by only one or two residues. One of the peptides, SC426, had nanomolar binding affinity ( K D =6.6±2.6 n m ) to MDM2, and exhibited stronger inhibitory activity on the proliferation of HCT116 cells (p53‐wild type) and SW480 cells (p53‐mutant) than that of nutlin‐3a. Binding mode analysis of the designed peptide at MDM2 suggests that the conserved “FWL” epitope was buried in the hydrophobic binding pocket, and the residues located at the periphery of the binding site contributed to the high binding affinity of SC426. Overall, in silico design of miniproteins with therapeutic potential through epitope grafting to the naturally occurring constrained peptide is an effective strategy.