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

Authors


  • We thank L. Bayer, S. Granata, A. Sihorsch, and S. Herok-Schöpper for synthetic assistance, V. Brachvogel, A. Liesum, and P. Lönze for support with X-ray structure determination, and Dr. M. Lorenz for discussions.

Abstract

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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).

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