In Silico Studies of Tumor Targeted Peptide-Conjugated Natural Products for Targeting Over-Expressed Receptors in Breast Cancer Cells Using Molecular Docking, Molecular Dynamics and MMGBSA Calculations

Lucy R Hart,Charlotta G Lebedenko,Ipsita A Banerjee,Saige M Mitchell,Rachel E Daso

doi:10.3390/app12010515

Abstract

In this work, in silico studies were carried out for the design of diterpene and polyphenol-peptide conjugates to potentially target over-expressed breast tumor cell receptors. Four point mutations were induced into the known tumor-targeting peptide sequence YHWYGYTPQN at positions 1, 2, 8 and 10, resulting in four mutated peptides. Each peptide was separately conjugated with either chlorogenate, carnosate, gallate, or rosmarinate given their known anti-tumor activities, creating dual targeting compounds. Molecular docking studies were conducted with the epidermal growth factor receptor (EGFR), to which the original peptide sequence is known to bind, as well as the estrogen receptor (ERα) and peroxisome proliferator-activated receptor (PPARα) using both Autodock Vina and FireDock. Based on docking results, peptide conjugates and peptides were selected and subjected to molecular dynamics simulations. MMGBSA calculations were used to further probe the binding energies. ADME studies revealed that the compounds were not CYP substrates, though most were Pgp substrates. Additionally, most of the peptides and conjugates showed MDCK permeability. Our results indicated that several of the peptide conjugates enhanced binding interactions with the receptors and resulted in stable receptor-ligand complexes; Furthermore, they may successfully target ERα and PPARα in addition to EGFR and may be further explored for synthesis and biological studies for therapeutic applications.

Highlights

Peptide-based cancer therapies are gaining importance, as they exhibit high biocompatibility compared to traditional chemotherapeutics and can be used to target cancer cells [1]
To further enhance tumor targeting and increase potency, each of the peptides were conjugated with the polyphenols chlorogenic acid (CGA), carnosic acid (CSA), gallic acid (GLA), and rosmarinic acid (RMA), each of which are well-known for their inherent anticancer properties
We have shown that the peptide sequence YHWYGYTPQN, previously known to bind to epidermal growth factor receptor (EGFR), is capable of binding to ERα and PPARα, making it suitable for targeting multiple over-expressed receptors in tumor cells

Summary

Introduction

Peptide-based cancer therapies are gaining importance, as they exhibit high biocompatibility compared to traditional chemotherapeutics and can be used to target cancer cells [1]. Tumor cell targeting can be accomplished by developing specific peptide sequences for several components typically overexpressed in cancer cells, such as receptors, integrins on tumor blood vessels, extracellular matrix components, and tumor-associated macrophages [2,3]. Molecular modeling and computational methods are being increasingly used to examine binding interactions and screen small molecules and peptides for developing more efficient and targeted compounds [4]. Phe and Asp residues were used to target overexpressed PTP1B and SHP2 phosphatases in breast cancer cells; the peptides were shown by molecular modeling techniques to bind to the phosphatases and demonstrated inhibition against MCF-7 breast tumor cells [5]. Computational methods were used to predict tumor-targeting ability of peptides for the epidermal growth factor receptor (EGFR) [6]. Peptide vaccines are an additional type of peptide-based cancer therapy, used to activate tumor-associated antigenspecific immune responses through processes such as targeting major histocompatibility complexes (MHCs) in tumor-associated antigen-presenting cells [7]

Methods

Results

Conclusion