Fragment Deconstruction of Small, Potent Factor Xa Inhibitors: Exploring the Superadditivity Energetics of Fragment Linking in Protein-Ligand Complexes

被引：45

作者：

Nazare, Marc ^{[1
]}

Matter, Hans ^{[1
]}

Will, David W. ^{[1
]}

Wagner, Michael ^{[1
]}

Urmann, Matthias ^{[1
]}

Czech, Joerg ^{[1
]}

Schreuder, Herman ^{[1
]}

Bauer, Armin ^{[1
]}

Ritter, Kurt ^{[1
]}

Wehner, Volkmar ^{[1
]}

机构：

[1] Sanofi Aventis Deutschland GmbH, R&D, D-65926 Frankfurt, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2012年 / 51卷 / 04期

关键词：

additivity; drug discovery; fragment linking; molecular recognition; noncovalent interactions; CATION-PI INTERACTIONS; 2-CARBOXYINDOLE SCAFFOLD; CRYSTAL-STRUCTURE; LEAD DISCOVERY; BINDING MODES; DESIGN; CRYSTALLOGRAPHY; SUBSTITUENTS; GENERATION; PRINCIPLES;

D O I：

10.1002/anie.201107091

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

More than just the sum of its parts: The superadditivity effect of fragment linking on ÎG was quantified by deconstructing two fXa inhibitors with congeneric fragments, but different linkers. By connecting both fragments with a single bond, a high linker contribution ÎGlink of -14.0 kJ mol-1 results, which corresponds to an improvement in affinity by around 2.5 orders of magnitude relative to the sum of fragment ÎG values (see picture). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

引用

页码：905 / 911

页数：7

共 10 条

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