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.
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Published in Khimiya Geterotsiklicheskikh Soedinenii, 2022, 58(8/9), 412–420
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Obernikhina, N.V., Kachaeva, M.V., Kachkovsky, O.D. et al. In silico Study of Conjugated Nitrogen Heterocycles Affinity in their Biological Complexes. Chem Heterocycl Comp 58, 412–420 (2022). https://doi.org/10.1007/s10593-022-03107-5
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DOI: https://doi.org/10.1007/s10593-022-03107-5