Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors

M. M. Neaz, F. A. Pasha, M. Muddassar, So Ha Lee, Taebo Sim, Jung Mi Hah, Seung Joo Cho

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11 Citations (Scopus)

Abstract

The growth and metastasis of solid tumors are dependent on angiogenesis. The vascular endothelial growth factor (VEGF) is of particular interest since it is essential for angiogenesis. The development of novel inhibitors of VEGF receptor type 2 (VEGFR-2) is important. Quantitative structure-activity relationship (QSAR) studies were performed to understand the structural factors affecting inhibitory potency of 4-aryl-5-cyano-2-aminopyrimidines. Pharmacophore models indicate that the importance of steric and hydrogen bond acceptor groups. The best-fitted pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Both CoMFA (q 2 = 0.62, r 2 = 0.87, and r 2 predictive = 0.7) and CoMSIA (q 2 = 0.54, r 2 = 0.86, and r 2 predictive = 0.61) gave reasonable results. Factors such as steric bulkiness, electrostatic effect, and hydrogen bond acceptor were found to be important for the inhibitory activity. It is suggested that negatively charged, bulky H-bond accepting groups around the piperazine nitrogen would enhance inhibition against VEGFR-2.

Original languageEnglish
Pages (from-to)127-142
Number of pages16
JournalMedicinal Chemistry Research
Volume18
Issue number2
DOIs
Publication statusPublished - 2009 Mar

Keywords

  • 3D-QSAR
  • CoMFA
  • CoMSIA
  • Drug design
  • Pharmacophore
  • VEGFR

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Neaz, M. M., Pasha, F. A., Muddassar, M., Lee, S. H., Sim, T., Hah, J. M., & Cho, S. J. (2009). Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors. Medicinal Chemistry Research, 18(2), 127-142. https://doi.org/10.1007/s00044-008-9113-4