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

Nazaré Marc | Zendy; Matter Hans | Zendy; Will David W. | Zendy; Wagner Michael | Zendy; Urmann Matthias | Zendy; Czech Jörg | Zendy; Schreuder Herman | Zendy; Bauer Armin | Zendy; Ritter Kurt | Zendy; Wehner Volkmar | Zendy

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

Author(s) -

Nazaré Marc,

Matter Hans,

Will David W.,

Wagner Michael,

Urmann Matthias,

Czech Jörg,

Schreuder Herman,

Bauer Armin,

Ritter Kurt,

Wehner Volkmar

Publication year - 2012

Publication title -

angewandte chemie international edition

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.831

H-Index - 550

eISSN - 1521-3773

pISSN - 1433-7851

DOI - 10.1002/anie.201107091

Subject(s) - superadditivity , fragment (logic) , deconstruction (building) , chemistry , ligand (biochemistry) , linker , stereochemistry , computer science , mathematics , biochemistry , biology , algorithm , mathematical economics , ecology , receptor , operating system

More than just the sum of its parts : The superadditivity effect of fragment linking on Δ G 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 Δ G link 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 Δ G values (see picture).

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