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In silico STUDY OF CONJUGATED NITROGEN HETEROCYCLES AFFINITY IN THEIR BIOLOGICAL COMPLEXES

Nataliya V. Obernilhina, Maryna V. Kachaeva, Oleksiy D. Kachkovsky, Volodymyr S. Brovarets
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Abstract


For the estimation of the biological affinity of nitrogen-containing π-conjugated heterocyclic systems toward amino acid residues in proteins, the fragment-to-fragment approach was proposed. Two mechanisms of complexation between the heterocycle molecule with different donor/acceptor properties and the amino acid residue in the active part of the protein biomolecule were considered. One of these mechanisms is the π-stacking interaction and the other is formation of hydrogen bonds with model amino acid residues. It was found that heterocycles with a π-conjugated electron-acceptor moiety form a more stable heterocycle–biomolecule complex with protein fragments. Nitrogen-containing conjugated heterocycles with several nitrogen atoms form poly-hydrogen-bonded complexes. The stabilization energy of complexes with two pyrimidine–biomolecule hydrogen bonds increases by 4–6 kcal/mol compared to similar complexes with one hydrogen bond. Hydrophobic interactions are much more sensitive to the donor-acceptor properties of heterocycles in the formation of hydrogen-bonded complexes than in the formation of π-stacked complexes. The hydrophobic effect in the fragment-to-fragment approach allows us to see the values of the stabilization energies of the heterocycle–biomolecule complexes as close as possible to the experimentally studied biological systems.


Keywords


biological affinity (φ0 parameter); fragment-to-fragment approach; heterocycle–biomolecule complex; hydrogen bonding; hydrophobic effect; π-stacking interaction

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