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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).