Molecular Recognition at the Active Site of Catechol-O-Methyltransferase: Energetically Favorable Replacement of a Water Molecule Imported by a Bisubstrate Inhibitor

被引：37

作者：

Ellermann, Manuel ^{[2
]}

Jakob-Roetne, Roland ^{[1
]}

Lerner, Christian ^{[1
]}

Borroni, Edilio ^{[1
]}

Schlatter, Daniel ^{[1
]}

Roth, Doris ^{[1
]}

Ehler, Andreas ^{[1
]}

Rudolph, Markus Georg ^{[1
]}

Diederich, Francois ^{[2
]}

机构：

[1] F Hoffmann La Roche & Cie AG, Praklin Forsch, Div Pharma, CH-4070 Basel, Switzerland

[2] ETH, Organ Chem Lab, CH-8093 Zurich, Switzerland

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2009年 / 48卷 / 48期

关键词：

drug discovery; enzymes; inhibitors; medicinal chemistry; structure-activity relationships; NUCLEIC-ACID CONFORMATIONS; CRYSTAL-STRUCTURE; BOUND WATER; BINDING; COMT; PREORGANIZATION; CLASSIFICATION; BIOCHEMISTRY; METHYLATION; STABILITY;

D O I：

10.1002/anie.200904410

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The import business: The binding mode of highly potent bisubstrate inhibitors of catechol-O-methyltransferase (COMT) has been elucidated by X-ray crystal structures of ternary complexes with COMTand a Mg2+ ion (see picture). A single ligand-imported water molecule is replaced, with a gain in binding free enthalpy of at least -1.8 kcal mol-1 compensating the costs of the energetically unfavorable conformation of the ligand in the bound state. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

引用

页码：9092 / 9096

页数：5

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