Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery.

Hayk Gasparyan,Ahmed K Farag,Sarah Albogami,Mohammed M Ghoneim,Smbat Gevorgyan,Ahmed A B Mohamed,Mohammad M Al-Sanea,Ashraf K El-Damasy,Garri Chilingaryan,Arsen Sargsyan,Sargis Hovhannisyan,Narek Abelyan

doi:10.3390/life11101070

Abstract

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors’ chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.

Highlights

Molecular docking of potential vascular endothelial growth factor receptor 2 (VEGFR-2) binding compounds retrieved from previous stages was performed using the ICM-PRO [23] v. 3.9-2b software
Significant efforts have been made in the R&D of VEGFR2 inhibitors regarding anti-angiogenic activity, with several compounds being approved as drugs
ZINC33268577 and ZINC1162830, which were derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione, respectively, demonstrated a potency as VEGFR2 inhibitors, in comparison to tivozanib, which was recently approved by the FDA for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) and was a potent, selective inhibitor of VEGFRs, including VEGFR2

Summary

Introduction

Despite the fact that multiple VEGFR-2 inhibitors have already been discovered, the endogenous and acquired resistance of the protein and the wide range of side effects of existing drug compounds still remain critical issues leading to short-term clinical effects and failure of antiangiogenic drugs [18,19]. These issues are associated with the fact that, due to the high structural similarity of VEGFR proteins family, VEGFR2 binding small molecules lack selectivity and can interact with all of the other VEGF family receptors. VEGFR-20 s catalytic domain where interaction with the small molecule inhibitors occurs, has a high structural similarity to the other tyrosine kinase receptors, such as the platelet-derived growth factor receptors (PDGFRs), and the colony-stimulating factor 1 receptor (CSF1R), as well as fms such as tyrosine kinase 3 (FLT-3), c-Kit, etc., that can cause unpredicted reactions from side effects

Methods

Results

Conclusion