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

Abstract

More than just the sum of its parts: The superadditivity effect of fragment linking on ΔG 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 ΔGlink 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 ΔG values (see picture). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.