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Ukr. Bioorg. Acta 2021, Vol. 16, N1, 34-43.

In silico study the interaction of heterocyclic bases with peptide moieties of proteins in «fragment-to-fragment» approach

Yevheniia S. Velihina1, Nataliya V. Obernikhina2*, Stepan G. Pilyo1, Maryna V. Kachaeva1, Oleksiy D. Kachkovsky1

1V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2O. O. Bogomolets National Medical University, 13 Shevchenko Blvd., Kyiv, 01601, Ukraine

tel.: +380-96-225-7764; e-mail: nataliya.obernikhina@gmail.com

ABSTRACT
The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the «fragment-to-fragment» approach. The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept] complexes formed by the π,π-stacking interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids (-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3 with a «free» peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced biological activity in vitro studies.

KEYWORDS
fragment-to-fragment approach; peptide bond; biological affinity; [Pharm-BioM] complex; π,π-stacking interaction; hydrogen bonding.

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