V. K. Kibirev¹, T. V. Osadchuk², O. P. Kozachenko², V. Kholodovych³, O. D. Fedoryak², V. S. Brovarets²

¹Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: kibirev@biochem.kiev.ua;
²Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv;
³Rutgers University, Newark, USA

A series of novel non-peptidic furin inhibitors with values of inhibitory constants (K_i) in the range of 0.74-1.54 μM was obtained by interactions of aminoguanidine hydrocarbonate with three diaryldicarbaldehydes. Correspondingly p-hydroquinone, piperazine and adipic acid were used as linkers between their benzene moieties. Docking studies of these new inhibitors into recently published 3D-structure of human furin (PDB code 4OMC) showed that they were able to interact with subsites S1 and S4 of the enzyme. The overall arrangement of bisamidinohydrazones into furin active site was similar to the position of the ligand co-crystallized with a protease. Observations obtained with molecular modeling allowed further guidance into chemical modifications of the synthesized inhibitors which improve their inhibitory activity.