RESUMO
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.
Assuntos
Furina/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Adipatos/química , Aldeídos/química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Furina/química , Guanidinas/química , Humanos , Hidrazonas/química , Hidroquinonas/química , Piperazina , Piperazinas/química , Inibidores de Proteases/síntese química , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Involvement of protein kinase CK2 (2.7.11.1) in modulation of live cells trans-plasma membrane electron transport was first discovered. Using human erythrocytes a decrease of plasma membrane redox system (PMRS) activity is shown under the action of specific protein kinase CK2 inhibitors. Using inhibitory analysis the activity regulation of human erythrocytes PMRS by Ca(2+)-dependent and Ca(2+)-independent mechanisms were investigated. It was shown that functional Ca(2+)-antagonists (nitrendipine and calmidazolium) significantly increased, and functional Ca(2+)-agonists to some extent reduced or did not affect the trans-plasma membrane electron transport in these cells.
