Efficient Stacking on Protein Amide Fragments

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.

Investigation of the complexation of natZr(iv) and 89Zr(iv) by hydroxypyridinones for the development of chelators for PET imaging applications

“…Such a geometry can be attributed to amide/heteroarene π stacking, with the amide nitrogen to HOPO ring center distance of 3.30 Å (Figure 1d) that matches the calculated distance for similar interaction reported between N -methylacetamide and pyridinone, providing additional stabilization to the complex. 43 …”

Heteroaromatic π-Stacking Energy Landscapes

“…Interaction patterns exhibited by aromatic heterocycles comprise hydrophobic, polar, hydrogen bonding, cation-π, 7−9 amid-π, 10 halogen-π, 11 and π-stacking interactions. 12 π-Stacking interactions have been investigated in detail by a wide range of experimental and computational methods: for benzene dimers, 13−16 in DNA 17 or in proteins.…”

A Monosaccharide‐Based Coin‐Cell Biobattery

“…The structure‐based design of the new BTCP analogue inhibitors was similarly built on the binding mode predefined by the salt bridge between the protonated tertiary amine and Glu 467′, and the inhibitor’s cyclohexyl ring, which establishes the orientation of the aromatic substituent toward the Z‐site. The derivatives shown in Table 1 were synthesized in order to investigate proper filling of the Z‐site in terms of polarity and size (compounds 4 – 7 ) and to optimize the postulated amide⋅⋅⋅π stacking with the flat peptide walls of the pocket (compounds 8 – 13 ) 37. Compounds 8 a and 10 – 13 a were substituted with five‐membered heteroaromatic linkers (Ar 1 ) featuring different electronic properties and bend angles between the two scaffold exit vectors 38.…”

“…In the T. brucei TR complex, the pyrrole moiety of the indole substituent is oriented parallel to the amide bond of Gly 112 and Met 113 and gains energy from amide⋅⋅⋅π stacking interactions (Figure 5). 37 The overlay of the two active sites reveals that the ligand can also be complexed with its indole ring turned by 180° (Figure 6 SI). This conformation is less optimal for dipolar amide⋅⋅⋅π stacking interactions, but instead, a C‐H⋅⋅⋅π interaction with Met 113 (Cα) is formed.…”