Structure-based inhibitory peptide design targeting peptide-substrate binding site in EGFR tyrosine kinase.

Laszlo Buday,Farial Tavakoli,Mohamad Reza Ganjalikhany

doi:10.1371/journal.pone.0217031

Laszlo Buday, Farial Tavakoli + Show 1 more

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https://doi.org/10.1371/journal.pone.0217031

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Journal: PloS one	Publication Date: May 22, 2019
Citations: 11	License type: CC BY 4.0

Affiliation: University of Isfahan

Abstract

EGFR (epidermal growth factor receptor) plays the critical roles in the vital cell activities, proliferation, differentiation, migration and survival in response to polypeptide growth factor ligands. Aberrant activation of this receptor has been demonstrated in many human cancers, particularly in non-small cell lung carcinoma (NSCLC). L858R point mutation is the most common oncogenic mutation in EGFR tyrosine kinase domain in patients with EGFR-mutated NSCLC. A feedback inhibitor of EGFR is MIG6 molecule which binds peptide-substrate binding site of the receptor and leads to degradation of activated EGFR. In this in silico study, the peptide-substrate binding site of EGFRL858R mutant has been targeted to inhibit it using molecular docking, MD simulation and MM-PBSA method. Finally, physicochemical properties of the designed peptides have been evaluated. A peptide library was provided composed of 31 peptides which were designed based on the MIG6 structure. The results indicated that, two peptides were able to inhibit EGFRL858R mutant selectively. This computational study could be helpful in designing novel inhibitory peptides to inhibit oncogenic EGFR mutants which do not respond to available EGFR TKIs.

Highlights

The human epidermal growth factor receptor (EGFR) family that contains four closely related receptors (EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4) plays pivotal roles in the regulation of cell proliferation, differentiation, migration, and survival in response to polypeptide growth factor ligands
The results were compared with the crystal structures of wild type EGFR (WT-EGFR) and EGFRL858R in complex with MIG6-pYpY (PDB IDs: 4ZJV and 4R3R respectively) and docked EGFR-MIG6YY complexes
The results indicated that peptides 5, 10 and 26, have significant binding affinity to EGFRL858R than WT-EGFR, compared to MIG6-YY (Table 2)

Summary

Introduction

The human epidermal growth factor receptor (EGFR) family that contains four closely related receptors (EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4) plays pivotal roles in the regulation of cell proliferation, differentiation, migration, and survival in response to polypeptide growth factor ligands. Overexpression or mutations of EGFR has been demonstrated in tumor cell formation and proliferation in some of human cancers such as liver, breast, stomach, colorectal cancers and in glioblastoma and non-small cell lung carcinoma (NSCLC) [1,2,3,4]. EGFR is composed of an extracellular ligand receptor, a transmembrane region, and an intracellular tyrosine kinase domain. Once ligand binds the receptor, EGFR activates and forms an asymmetric dimer in tyrosine kinase domain, in which the C-lobe of the kinase domain (activator EGFR) contacts to the N-lobe of the receiver EGFR and stabilizes it in the active state conformation. Active EGFR leads to signaling process through RAS-MAP kinase, PI3K-AKT and other pathways [1, 5].

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