Understanding the Impact of the P-loop Conformation on Kinase Selectivity

被引：80

作者：

Guimaraes, Cristiano R. W. ^{[1
]}

Rai, Brajesh K. ^{[2
]}

Munchhof, Michael J. ^{[1
]}

Liu, Shenping ^{[3
]}

Wang, Jian ^{[1
]}

Bhattacharya, Samit K. ^{[1
]}

Buckbinder, Leonard ^{[4
]}

机构：

[1] Pfizer Global Res & Dev, Worldwide Med Chem Dept, Groton, CT 06340 USA

[2] Pfizer Global Res & Dev, Computat Sci Ctr Emphasis, Groton, CT 06340 USA

[3] Pfizer Global Res & Dev, Dept Struct Biol & Biophys, Groton, CT 06340 USA

[4] Pfizer Global Res & Dev, CVMED Target Explorat, Groton, CT 06340 USA

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2011年 / 51卷 / 06期

关键词：

PROTEIN-KINASE; INHIBITORS; MAP4K4; DESIGN;

D O I：

10.1021/ci200153c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This work addresses the link between selectivity and an unusual, folded conformation for the P-loop observed initially for MAP4K4 and subsequently for other kinases. Statistical and computational analyses of our crystal structure database demonstrate that inhibitors that induce the P-loop folded conformation tend to be more selective, especially if they take advantage of this specific conformation by interacting more favorably with a conserved Tyr or Phe residue from the P-loop.

引用

页码：1199 / 1204

页数：6

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