Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2.

Frangky Sangande,Daryono Hadi Tjahjono,Elin Julianti

doi:10.3390/ijms21207779

Abstract

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence of VEGF up-regulation independent of EGFR leads to cancer cell resistance to anti-EGFR. Therefore, a therapeutic approach targeting EGFR and VEGFR2 simultaneously may improve the outcome of cancer treatment. The present study was designed to identify potential compounds as a dual inhibitor of EGFR and VEGFR2 by the computational method. Firstly, the ligand-based pharmacophore model for each target was setup to screen of ZINC database of purchasable compounds. The hit compounds obtained by pharmacophore screening were then further screened by molecular docking studies. Taking erlotinib (EGFR inhibitor) and axitinib (VEGFR2 inhibitor) as reference drugs, six potential compounds (ZINC08398597, ZINC12047553, ZINC16525481, ZINC17418102, ZINC21942954, and ZINC38484632) were selected based on their docking scores and binding interaction. However, molecular dynamics simulations demonstrated that only ZINC16525481 and ZINC38484632 which have good binding free energy and stable hydrogen bonding interactions with EGFR and VEGFR2. The result represents a promising starting point for developing potent dual tyrosine kinases inhibitor of EGFR and VEGFR2.

Highlights

Tyrosine kinases are enzymes that catalyze the phosphorylation of tyrosine residues in proteins and activate signal transduction pathways that play an important role in cell proliferation, differentiation, migration, metabolism, and apoptosis
A total of 10 pharmacophore models were obtained for each target and the first model was selected as the best model based on its AUC value of receiver operating characteristic (ROC)
The selected pharmacophore model of Epidermal growth factor receptor (EGFR) consists of one hydrophobic group, three aromatic groups, two hydrogen bond acceptors, and one hydrogen bond donor, while the selected pharmacophore model of vascular endothelial growth factor receptor 2 (VEGFR2) consists of one hydrophobic group, one aromatic group, one hydrogen bond acceptor, and one hydrogen bond donor (Figure 2)

Summary

Introduction

Tyrosine kinases are enzymes that catalyze the phosphorylation of tyrosine residues in proteins and activate signal transduction pathways that play an important role in cell proliferation, differentiation, migration, metabolism, and apoptosis. Epidermal growth factor receptor (EGFR) is a member of tyrosine kinases and is commonly overexpressed in some types of cancer, such as non-small-cell lung cancer, breast, esophageal, cervical, and head and neck cancer [2]. EGFR activation will increase the expression of vascular endothelial growth factor (VEGF). VEGFR is a member of the tyrosine kinase group that demonstrates a role in cancer growth through the angiogenesis mechanism, it is an ideal drug target in cancer therapy. Overexpression of VEGF by this pathway is associated with cancer cell resistance to anti-EGFR [6]. Therapeutic approaches using drugs that inhibit both EGFR and VEGFR2 can increase the efficiency of cancer therapy and overcome the resistance problem [7,8]. Benzimidazole [12] and phthalazine derivatives [13] have been tested for their activity against EGFR and VEGFR2

Methods

Results

Conclusion