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Efficient Stacking on Protein Amide Fragments

Authors

  • Michael Harder,

    1. Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland)
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  • Dr. Bernd Kuhn,

    Corresponding author
    1. Discovery Chemistry, F. Hoffmann–La Roche AG, Grenzacherstrasse 124, Bau 92, 4070 Basel (Switzerland)
    • Discovery Chemistry, F. Hoffmann–La Roche AG, Grenzacherstrasse 124, Bau 92, 4070 Basel (Switzerland)
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  • Prof. Dr. François Diederich

    Corresponding author
    1. Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland)
    • Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland)
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Abstract

The less polar π-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on amide groups of a large number of heteroarenes that are relevant to medicinal chemistry. From this study, we discern that the stacking energy of an aromatic ligand substituent can be improved by: 1) orienting the fragment dipole vector such that it is aligned in an antiparallel fashion with the dipole of the interacting protein amide group, 2) increasing its dipole moment, and 3) decreasing its π-electron density. These guidelines should be helpful to more rationally exploit this interaction type in future structure-based drug design.

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