Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones

Abstract

Stacking interactions can be important enthalpic contributors to drug binding. Among the less well-studied stacking interactions are those occurring between an arene and the π-face of an amide group. Given the ubiquity of heterocycles in drugs, combined with the abundance of amides in the protein backbone, optimizing these noncovalent interactions can provide a potential route to enhanced drug binding. Previously, Diederich et al. (ChemMedChem 2013, 8, 397-404) studied stacked dimers of a model amide with a set of 18 heterocycles, showing that computed interaction energies correlate with the dipole moments of the heterocycles and providing guidelines for the optimization of these interactions. We considered stacked dimers of the same model amide with a larger set of 28 heterocycles common in pharmaceuticals, by using more robust ab initio methods. While the overall trends in these new data corroborate many of the results of Diederich et al., these data provide a more refined view of the nature of amide stacking interactions. We present a robust scoring function for amide stacking interaction energies based on the molecular dipole moment and strength of the electric field above the arene.

Activation Effects of Carnosine- and Histidine-Containing Dipeptides on Human Carbonic Anhydrases: A Comprehensive Study

“…Figure 2A shows the putative complex for the most active d-carnosine within the CA II catalytic cavity and reveals that the ligand's imidazole ring assumes a pose superimposable with that observed for the co-crystallized histidine and is surrounded by a set of interacting residues with which it can elicit π-π stacking plus H-bonds (such as Asn62, His64, Asn67, Gln92 and, to minor extent His94). The involvement of amide containing side chains seems to confirm the stabilizing role of stacking interactions between amide and heteroaryl moieties as recently investigated [20].…”

Structure and Morphology of Light-Reflecting Synthetic and Biogenic Polymorphs of Isoxanthopterin: A Comparison

“…Nonetheless, this offset brings about an antiparallel arrangement of both the carbonyl bonds along the a axis (a motif that has been observed in a carboxylic acid crystal structure), [66][67][68] and an NH/π binding motif of the NH 2 group with the pyrazine ring. [69][70][71][72][73] Figure 7 (A) Molecular packing of two neighboring H-bonded layers of biogenic β isoxanthopterin, viewed perpendicular to the layer plane, displaying molecular overlap. (B) A magnified view of A, emphasizing the antiparallel arrangement of C=O carbonyl bonds and the NH/π interaction.…”

Synthesis, Characterization, and Fluorescence Properties of Two New Heterocyclic Compounds Containing 1,5-Dioxaspiro Group

“…A novel insecticide with pyridine group had a strong effect on imidacloprid (IMI)-resistant rice pests [3]. The complexes with thiosemicarbazide motif possessed antimicrobial activity [4]. Three heterocyclic homoprostanoids derivatives showed antioxidant and anti-inflammatory activity [5].…”