Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors |
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Authors: | M. M. Neaz F. A. Pasha M. Muddassar So Ha Lee Taebo Sim Jung-Mi Hah Seung Joo Cho |
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Affiliation: | (1) Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology, P.O. Box 131, Seoul, 130-650, South Korea;(2) Research Center for Resistant Cells, Chosun University, Gwangju, 501-759, Korea;(3) College of Medicine, Chosun University, Gwangju, 501-759, Korea |
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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. |
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Keywords: | CoMFA CoMSIA Drug design Pharmacophore VEGFR 3D-QSAR |
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