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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Harder M,Kuhn B,Diederich Fdoi
10.1002/cmdc.201200512subject
Has Abstractpub_date
2013-03-01 00:00:00pages
397-404issue
3eissn
1860-7179issn
1860-7187journal_volume
8pub_type
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