De novo Design of Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors†

doi:10.7503/cjcu20130642

Abstract

Abstract:

Protein tyrosine kinase(PTK) is an especially important target for anticancer drug design due to its crucial role in the modulation of growth factor signaling. Vascular endothelial growth factor receptor-2(VEGFR-2) tyrosine kinase plays a pivotal role in modulating angiogenesis, as well as the proliferation and migration of endothelium. Compounds that inhibit the activity of VEGFR-2 tyrosine kinase are potential chemotherapeutics to treat tumors. In this study, based on the crystal structure of VEGFR-2 tyrosine kinase, de novo drug design was employed to develop a series of indole compounds. Absorption, distribution, metabolism, excretion and toxicity(ADMET) and molecular docking were used to screen the designed compounds. Finally, ten molecules which have lower binding energy were obtained, a 10 ns molecular dynamics(MD) calculation was performed to study the complex of the compound which has the lowest binding energy and VEGFR-2 tyrosine kinase, and then the binding models were analyzed. These new chemical entities could be lead compounds for anticancer. This result will provide theoretical basis for molecular structure improvement, molecular design, and molecular synthesis of VEGFR-2 tyrosine kinase inhibitors.

Key words: Vascular endothelial growth factor receptor-2(VEGFR-2), Tyrosine kinase inhibitor, De novo drug design, Absorption,distribution,metabolism,excretion and toxicity(ADMET), Molecular docking

CLC Number:

O621

TrendMD:

KANG Congmin, ZHAO Xuhao, YU Yuqi, LÜ Yingtao. De novo Design of Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors^†[J]. Chem. J. Chinese Universities, 2014, 35(3): 550.

Figures/Tables 7

Fig.1 Work flow during the designing of VEGFR-2 tyrosine kinase inhibitors

Fig.2 VEGFR-2 tyrosine kinase and the key site

Fig.3 Sunitinib and the pharmacophore model

Fig.4 Structures of designed compounds

Table 1 Binding energy of designed compounds and sunitinib docked with VEGFR-2 tyrosine kinase

Compound	03_047	01_083	07_006	03_118	03_121	01_041	03_009	03_039	03_006	03_084	Sunitinib
E_b/(kJ·mol^-1)	-43.93	-43.51	-43.51	-42.68	-42.68	-42.26	-42.26	-42.26	-42.26	-42.26	-41.84

Fig.5 RMSD change of VEGFR-2 tyrosine kinase backbone atoms in MD simulation

Fig.6 Schematic plans of interactions between compound 003_047 and VEGFR-2 tyrosine kinase active cavity

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