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G.F. Kurakin Student, Faculty of General Medicine, Tver State Medical University E-mail: N.P. Lopina Ph.D. (Chem.), Department of Chemistry, Tver State Medical University G.E. Bordina Ph.D. (Biol.), Department of Chemistry, Tver State Medical University

Presently, the possibility of invention of flavonoid-based medicines for treatment of therapeutical, neurological, oncological diseases is actively studied. Herewith, antagonistic activity of flavonoids on adenosine receptors is described. A model of interaction between flavonoids and adenosine re-ceptors is necessary for the prediction of possible adenosine receptor-mediated effects of flavonoids and for development of new adenosine receptor antagonists on their basis. Conversely, up to date, receptor-based models of flavonoid binding to adenosine receptors are absent. Research objective: obtaining of a receptor-based computational model of flavonoid binding to adenosine receptors. Materials and methods. Ligand structures from databases PubChem and ZINC were used. Structures of A1 and A2A adenosine receptors were obtained from Protein Data Bank (PDB). A3 adenosine receptor was homology modelled using Swiss-Model server. The interactions between flavonoids and adenosine receptors were analysed using flexible docking on Galaxy7TM server. The binding energies were indirectly evaluated by pose ranges in Galaxy7TM docking results and were also calculated using KDEEP server based on neural network. For several flavonoids, the ligand-receptor interactions were additionally analysed using PoseView online service. Amino acid conservation was studied using ConSurf server and UniProt sequences. Results. The most flavonoids form a hydrogen bond with asparagine residue (Asn254 in А1, Asn253 in А2А, Asn250 in А3) of adenosine receptors. Other hydrogen bonds were present occasionally in a case of some flavonoids. All flavonoids form π-electronic and hydrophobic interactions with phenylalanine residue (Phe171 in А1, Phe168 in А2А, Phe168 in А3). Hydrophobic contacts with conserved isoleucine (Ile274 in A1 and A2A, Ile268 in A3) and leucine (Leu250 in A1, Leu249 in A2A, Leu246 in A3) residues were also present. These interactions resemble those in the case of xanthine-based antagonists. Obtained models accord with experimental data and allows to range flavo-nois by affinity to certain types of adenosine receptors with feasible accuracy. In our models, selectivity of flavonoids toward certain types of adenosine receptors and reinforcement of binding under flavonoid alkylation were determined by the form of hydrophobic pockets of adenosine receptors. Conclusion. The receptor-based model of flavonoid binding to adenosine receptors was obtained. It can be used for the design of adenosine re-ceptor-targeted drugs and as starting point for modelling of interactions between other phytochemicals and adenosine receptors.

adenosine receptors
computational modelling
receptor-based model

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