Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.
Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.
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DOI：
10.1021/jm8010299
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发表时间：
2008-12-25
影响因子：
7.3
通讯作者：
Abagyan R
中科院分区：
文献类型：
--
作者：
Kufareva I;Abagyan R
II型激酶抑制剂代表一类化学品，其将其靶激酶捕获在非活性（所谓DFG-出）状态，占据邻近ATP结合位点的疏水口袋。这些化合物通常比靶向活性DFG-in激酶构象的那些更特异。不幸的是，新的II型支架的发现提出了相当大的挑战，部分原因是缺乏相容的激酶结构使得基于结构的方法不适用。我们提出了一个计算协议转换成准确的和特定的模型，其II型结合状态的多种可用的DFG-在各种激酶的结构（约70%的哺乳动物结构激酶组）。该模型被描述为缺失环asp-Phe-gly-IN（海豚）激酶模型，在各种抑制剂发现应用中表现出卓越的性能，包括化合物位姿预测、筛选和计算机活性分析。鉴于DFG-in结构的丰富性，所提出的方法为在激酶组范围内发现靶向非活性激酶状态的特定分子提供了可能性。
Type-II kinase inhibitors represent a class of chemicals that trap their target kinases in an inactive, so-called DFG-out, state, occupying a hydrophobic pocket adjacent to the ATP binding site. These compounds are often more specific than those targeting active, DFG-in, kinase conformations. Unfortunately, the discovery of novel type-II scaffolds presents a considerable challenge, partly because the lack of compatible kinase structures makes structure-based methods inapplicable. We present a computational protocol for converting multiple available DFG-in structures of various kinases (∼70% of mammalian structural kinome) into accurate and specific models of their type-II-bound state. The models, described as Deletion-Of-Loop asp-PHe-gly-IN (DOLPHIN) kinase models, demonstrate exceptional performance in various inhibitor discovery applications, including compound pose prediction, screening, and in silico activity profiling. Given the abundance of the DFG-in structures, the presented approach opens possibilities for kinome-wide discovery of specific molecules targeting inactive kinase states.
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影响因子：
7.3
作者：
Hasegawa, Masaichi;Nishigaki, Naohiko;Cheung, Mui
通讯作者：
Cheung, Mui
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
14.8
作者：
Liu, Y;Gray, NS
通讯作者：
Gray, NS
影响因子：
11.5
作者：
Ahmad, T;Eisen, T
通讯作者：
Eisen, T
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M