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

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.

Keywords: VEGFR2; drug discovery; molecular dynamics simulations; tivozanib; virtual screening.

Figure 1

(A) Similarity analysis of the identified 53 chemical compounds to the co-crystallized ligand (tivozanib). (B) Clusterization of the 53 identified compounds with higher docking scores in comparison to tivozanib. For each cluster, ZINC ID of the representative compound with highest docking score is highlighted in black.

Figure 2

RMSD values of the 5 studied compounds and co-crystalized ligand. Black – tivozanib, red—ZINC114898570, green—ZINC1162830, blue—ZINC1033964, yellow—ZINC33268577, brown—ZINC65063291.

Figure 3

Binding poses, 2D interaction diagrams and interaction binding free energies (GBSA and PBSA, presented values are in kcal/mols) of tivozanib and 5 selected compounds.

Figure 4

The common interacting amino acid residues of the ATP-binding site of VEGFR2 and their contribution to the interaction with the studied compounds and tivozanib in terms of binding energy.

Figure 5

Chemical similarity analysis of ZINC33268577 and ZINC1162830 with reference ligand (tivozanib).