Pharmacophore Generation and 3D-QSAR of Novel 2-(quinazolin-4- ylamino)-[1,4] Benzoquinone Derivatives as VEGFR-2 Inhibitors

Mahesh      Kumar Teli; Pradeep      Hanumanthappa; Rajanikant      G. Krishnamurthy

doi:10.2174/1570180811209050899

Abstract

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 are critical regulators of angiogenesis. The blockage of VEGFR-2 signaling by small molecule inhibitors has been shown to inhibit angiogenesis and tumor progression. The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of benzoquinone derivatives reported for VEGFR-2 inhibition. A five point pharmacophore model was developed with an excellent correlation coefficient value (r2 = 0.9395) along with good statistical significance as shown by the high Fisher ratio (F = 63.8). The model also exhibited good predictive power confirmed by the high value of the cross validated correlation coefficient (q2 = 0. 6228). The QSAR model suggests that hydrophobic character is crucial for the VEGFR-2 inhibitory activity, exhibited by these compounds and inclusion of hydrophobic substituent will enhance the VEGFR-2 inhibition. In addition to the hydrophobic character, H-bond donating groups and electron withdrawing groups positively contribute to the VEGFR-2 inhibition. Further, the pharmacophoric model was validated by ROC curve analysis and was employed for virtual screening to identify six potential VEGFR-2 inhibitors. The findings of this study provide a set of guidelines for designing compounds with better VEGFR-2 inhibitory potency.

Keywords: Vascular endothelial growth factor receptor-2, Cancer, 2-(quinazolin-4-ylamino)-[1, 4] benzoquinone derivatives, Pharmacophore, 3D-QSAR, vasculature, VEGFR-1, 4-aryl-5-cyano-2-aminopyrimidines inhibitors, pathogenesis, pharmacological activities