Molecular Design of VEGFR2 Inhibitors
VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) plays an essential role in the signal transduction pathway of angiogenesis; it serves as the key point of this signaling pathway. Activation of VEGFR2 can trigger a set of biological effects such as proliferation, migration and alternation of membrane permeability of endothelial cells. The growth of solid tumors has been proven to be an angiogenesisdependent process; they grow beyond a critical size by inducing new capillaries sprouting from preexisting blood vessels to fulfill nutrition, oxygen supply, essential regulatory factors and removal of metabolites. Recent studies show that direct inhibition of the kinase activity of VEGFR2 could result in the reduction of angiogenesis which in turn suppresses the growth of solid tumors. Rational drug design based on the structure of RTKs (Receptor Tyrosine Kinases) has provided a promising approach for anti-tumor drug discovery. There is now a general agreement that multi-targeted inhibition has a much greater potency than single-targeted inhibition, however, researchers could not predict the potential toxicity and side effects of multi-targeted inhibition since the human kinome is an extremely complicated network. Here comes the very special target VEGFR2. VEGFR2 is an RTK which locates exclusively on the membrane of vascular endothelial cells. Because of this special feature, selective inhibition of the kinase activity of VEGFR2 could favorably reduce the toxicity and side effects of RTK inhibitors. This contribution gives the basic idea of VEGFR2 structure-based drug design, a unique method of structure-based drug design and pharmacophorebased database screening, and a scoring function for hit compound evaluation.
Bian Li Peng Du Qing Shen Wei Fu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
国际会议
武汉
英文
316-324
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）