title: Synthesis, biological evaluation and docking of novel bisamidinohydrazones as non-peptide inhibitors of furin.
abstract: A series of novel non-peptidicfurin inhibitors with values of inhibitory constants (Ki) in the range of 0.74-1.54 μM was obtained by interactions of aminoguanidine hydrocarbonate with three diaryldicarbalde- hydes. Correspondingly p-hydroquinone, piperazine and adipic acid were used as linkers between their ben- zene 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.
authors.forename: V K
authors.initials: VK
authors.lastname: Kibirev
authors.forename: T V
authors.initials: TV
authors.lastname: Osadchuk
authors.forename: O P
authors.initials: OP
authors.lastname: Kozachenko
authors.forename: V
authors.initials: V
authors.lastname: Kholodovych
authors.forename: D
authors.initials: D
authors.lastname: Fedoryak
authors.forename: V S
authors.initials: VS
authors.lastname: Brovarets
mesh_terms: D000272:Adipates / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D045683:Furin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006146:Guanidines / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D006873:Hydroquinones / Q000737:chemistry; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000272:Adipates; D000447:Aldehydes; D006146:Guanidines; D006835:Hydrazones; D006873:Hydroquinones; D010879:Piperazines; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D000077489:Piperazine; C029900:adipic acid; D045683:Furin; C031927:hydroquinone