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Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)
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ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 76/253 (Pharmacology & Pharmacy)
Online ISSN: 1860-7187
January 29, 2013
VIP: Efficient Stacking on Protein Amide Fragments
Michael Harder, Bernd Kuhn,* François Diederich*
Amide groups are abundant in receptor binding sites, either as part of the protein backbone or in Gln/Asn side chains, but the optimal interaction of their π-surface with ligand groups is only poorly understood. In a collaboration between researchers at the ETH Zurich (Michael Harder, François Diederich) and F. Hoffmann–La Roche (Bernd Kuhn) extensive quantum chemical calculations and PDB database searches were used to characterize the stacking of N-methylacetamide, as a protein amide model system, on various heteroarenes. Relative orientations and distance dependencies between the interacting monomers, as well as substituent effects were studied in detail, revealing new guidelines helpful in structure-based drug design. The calculations show a good correlation between SCS-MP2 derived interaction energies and a simple interaction model based on dipolar interactions, making it easy to apply for medicinal chemists. Antiparallel alignment of the dipole vectors, decreasing π-electron density, and increasing strength of the dipole moment were found to improve the stacking energy of ligand heterocycles with protein amide groups.
Received November 4, 2012; published online January 25, 2013, DOI: 10.1002/cmdc.201200512.