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

Yevheniia Velihina,Oleksiy Kachkovsky,Stepan Pilyo,Nataliya Obernikhina,Maryna Kachaeva

doi:10.15407/10.15407/bioorganica2021.01.034

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.

Highlights

The heterocyclic ring systems containing both nitrogen and oxygen, such as substituted 1,3-oxazoles, are very suitable for use in drug design and library design, which has allowed the introduction of a number of novel pharmacological agents in medical practice
This paper presents the results of in-silico studies of the stability of the [Pharmophore-Peptide] complex formed between peptide moieties in a model protein and heterocycles as pharmacophores using the “fragment-to fragment” approach
In silico the theoretical analysis of the interaction between pharmacophore molecules based on bicyclic nitrogen heterocycles with model peptides shows that the stabilization of [Pharm-Pept] complexes is ensured by the, -stacking interactions of the pharmacophore molecule systems with the -peptide bond system

Summary

Introduction

The heterocyclic ring systems containing both nitrogen and oxygen, such as substituted 1,3-oxazoles, are very suitable for use in drug design and library design, which has allowed the introduction of a number of novel pharmacological agents in medical practice (see for example reviews [1,2]). Variation of the functional residues in the model molecule H3C-Y-H shows that the most stable [HB]complex of compounds 1 is formed with OH-group; a similar tendency is observed for a number of benzoanalogues 2, anellation of the compounds 1 increases the binding energy.

Results

Conclusion