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

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.

In Silico Study of Physicochemical Characteristics and Anticancer Potential of Peptides Derived from Salvia Hispanica

“…As shown in Table 4, PAP-3 displayed forming hydrogen bonds with Lys721 and Asp831. These hydrogen bonds have been reported previously by (Sangande et al, 2020). Particularly, the residue Asp831 is part of the DFG (Asp-Phe-Gly) motif which plays a key role in ATP binding and is relevant for the increased inhibitory activity of the receptors (Peng et al, 2013).…”

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

“…Thienyl-based VEGFR-2 inhibitors have been published, such as chalcone derivatives with thienyl moieties, which showed considerable VEGFR-2 inhibitory activities as well as activities against HUVEC cells as an angiogenesis cell model [ 14 ]. Several works about new VEGFR-2 inhibitors were disclosed, which indicate the clinical potential and importance of this research field [ 39 , 40 , 41 ]. Compound 1c also inhibited the receptor tyrosine kinase c-Kit, which is a cell growth promoting factor and a relapse risk enhancer in hepatoma [ 42 ].…”

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

“…Accumulating pieces of evidence have confirmed that VEGFR2 is closely related to EGFR and is involved in the development of multiple types of tumors [74,75]. Thus, the combination of VEGFR2 inhibitors and EGFR inhibitors can be promising in antitumor treatment.…”