CCR2: Characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach

被引:78
作者
Berkhout, TA
Blaney, FE
Bridges, AM
Cooper, DG
Forbes, IT
Gribble, AD
Groot, PHE
Hardy, A
Ife, RJ
Kaur, R
Moores, KE
Shillito, H
Willetts, J
Witherington, J
机构
[1] GlaxoSmithKline, Dept Discovery Chem, Harlow CM19 5AD, Essex, England
[2] GlaxoSmithKline, Dept Vasc Biol, Harlow CM19 5AD, Essex, England
[3] GlaxoSmithKline, Dept Gene Express Sci, Harlow CM19 5AD, Essex, England
关键词
D O I
10.1021/jm030862l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
引用
收藏
页码:4070 / 4086
页数:17
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