Molecular Interactions of Pyrazine-Based Compounds to Proteins

Pyrazine-based compounds are of great
importance in medicinal chemistry.
Due to their heteroaromatic nature, they uniquely combine properties
of heteroatoms (polar interactions) with the properties of aromatic
moieties (nonpolar interactions). This review summarizes results of
a systematic analysis of RCSB PDB database focused on important binding
interactions of pyrazine-based ligands cocrystallized in protein targets.
The most frequent interaction of pyrazine was hydrogen bond to pyrazine nitrogen atom as an acceptor,
followed by weak hydrogen bond with pyrazine hydrogen as donor. We
also identified intramolecular hydrogen bonds within pyrazine ligands,
π-interactions, coordination to metal ions, and few halogen
bonds in chloropyrazines. In many cases the binding mode of the pyrazine
fragment was complex, involving a combination of several interactions.
We conclude that pyrazine as a molecular fragment should not be perceived
as a simple aromatic isostere but rather as a readily interacting
moiety of drug-like molecules with high potential for interactions
to proteins.