RESUMEN
A substrate and inhibitor analysis of the thrombin interaction with synthetic peptide substrates and inhibitors of differing hydrophobicity and volume of the side amino acid residue, localized in the sub-centers thrombin S2 and S3 were carried out. The kinetic parameters of individual stages of the enzymatic reaction process (K(S), k2, k3) were estimated. It is shown that the efficiency of acylation and deacylation stages of the enzymatic reaction decreases with increasing hydrophobicity of the substituent in P2 as well as P3, at the same time the affinity of selected peptides toward enzyme is steadily increasing. With the aim to evaluate the hydrophobicity of compounds a LogP value was calculated and was made an attempt to compare them with the correspondent Ki values. Comparative kinetic analysis of Z-Arg-OMe and its uncharged analogue Z-Cit-OMe has shown the absence of uncharged analog hydrolysis, however, the mentioned citrulline derivate inhibits the hydrolysis of the charged analogue. These findings confirm the important role of hydrophobic moiety in the structure of thrombin inhibitors in preferential binding mode and inhibition of thrombin active side.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Péptidos/metabolismo , Trombina/antagonistas & inhibidores , Acilación , Inhibidores Enzimáticos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Péptidos/química , Relación Estructura-Actividad , Especificidad por Sustrato , Trombina/química , Trombina/metabolismoRESUMEN
Interaction of two groups of bioregulators, which oppositely affect activity of adenylate cyclase and phosphoinositide cellular signaling systems, with the Langmuir monolayer films made of natural lecithin was studied. Most significant influence on the structural and energy characteristics of lipid monolayers was revealed for the group of bioregulators, which inhibit polyphosphoinositide signaling system or/and activate adenylate cyclase signaling system. It is shown, that using the cluster analysis the bioregulators can be divided into two groups according to general orientation of their action on the considered systems of transduction of a signal.
Asunto(s)
Adenilil Ciclasas , Membrana Celular/metabolismo , Membranas Artificiales , Modelos Biológicos , Fosfatidilinositoles , Transducción de Señal , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/química , Membrana Celular/efectos de los fármacos , Análisis por Conglomerados , Metabolismo Energético/efectos de los fármacos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Preparaciones Farmacéuticas/administración & dosificación , Fosfatidilcolinas/química , Fosfatidilinositoles/antagonistas & inhibidores , Fosfatidilinositoles/química , Transducción de Señal/efectos de los fármacosRESUMEN
The influence of physical and chemical properties of some sites of transmembrane receptor domains on the receptors ability to interact with nonspecific antagonists was investigated mathematically. The properties of sites located in 3rd and 7th transmembrane domains are most likely to explain pharmacological characteristics of the receptors. The possibility of receptor blocking by nonspecific antagonists not by competing with agonists but by influencing the receptor conformation is discussed.
Asunto(s)
Receptores de Amina Biogénica/antagonistas & inhibidores , Animales , Sitios de Unión , Humanos , Ratas , Receptores de Amina Biogénica/química , Receptores de Amina Biogénica/metabolismoRESUMEN
Using experimental transcription model in vitro, and method of electron-topological calculations the elements of pharmacological and structural community have been found in the groups of physiologically active compounds (PAC), blocking and activating external cellular receptors. This finding confirms the necessity of subdivision special groups of bio-substrates blockators and activators for hierarchical classification, of PAC.