Molecular Docking and Preclinical Study of Five-Membered S,S-Palladaheterocycle as Hepatoprotective Agent.

Nail Salavatovich Akhmadiev,Valery Alekseevich Kataev,Rozaliia Akramovna Galimova,Albina Midkhatovna Galimova,Vnira Rakhimovna Akhmetova,Eduard Feliksovich Agletdinov,Veronika Radievna Khairullina,Askhat Gabdrahmanovich Ibragimov

doi:10.15171/apb.2019.079

Abstract

Purpose: In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle, inhibition of cytochromes P450 has been modeled by molecular docking of four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system. To obtain a deeper insight into biochemical aspects providing a basis for the therapeutic effects of five-membered palladacycles (as mixture of stereoisomers), a number of preclinical trials has been conducted Methods: 2D and 3D structures of palladaheterocycle stereoisomers were obtained via converting into SDF files by means of software MarvinSketch. Binding of palladaheterocycle at the active sites of cytochromes P450 2E1 and P450 2C9 has been studied by molecular docking using LeadIT 2.3.2. Hepatoprotective activity of palladaheterocycle at 2.5, 25 and 250 mg/kg doses has been studied based on a model of acute intoxication by CCl4 using in vivo methods. Results: By molecular docking it was identify amino acid fragments responsible for binding with palladacyclic isomers. The tested compound is comparable, in terms of its activity to the hepatoprotective drug SAM according to the in vivo and in vitro experiments such as animal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretory function, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liver antitoxic function (the latter has been determined based on the results of a hexobarbital control experiment). Conclusion: Taking into account results obtained in vivo, in vitro and in silico, it can be concluded that the five-membered S,S-palladaheterocycle effectively protect the liver against acute damage caused by CCl4 , via activation of catalase and glucuronyltransferase, as well as via inhibition of the oxidative stress enzymes.

Highlights

In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle, inhibition of cytochromes P450 has been modeled by molecular docking of four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system
Taking into account results obtained in vivo, in vitro and in silico, it can be concluded that the five-membered S,S-palladaheterocycle effectively protect the liver against acute damage caused by CCl4, via activation of catalase and glucuronyltransferase, as well as via inhibition of the oxidative stress enzymes
A noteworthy cluster of drugs based on enzymeligand interactions includes sulfur-containing derivatives and nitrogen-containing derivative, said cluster being represented by a wide range of pharmaceuticals and natural products.[9,10,11]

Summary

Introduction

Problems associated with hepatic disorders that lead to disruption of vital metabolic processes[1,2] are triggered by hepatitis or HIV viruses, mycotic infections, hemochromatosis, schistosomiasis, as well as by obesity and intoxication (alcohol, drugs, chemicals).[3,4,5] To restore of metabolic processes in the liver cells, various hepatoprotective agents with multidirectional bioregulation are traditionally utilized.[6]A modern approach is based on implementation of biochemical processes via binding drug molecules to a number of enzymatic systems, including the cytochrome P450 system and the other microsomal enzymes.[7,8]A noteworthy cluster of drugs based on enzymeligand interactions includes sulfur-containing derivatives (sulfides, sulfoxides, sulfones, thionic salts) and nitrogen-containing derivative (amines, amino acids, azaheterocycles), said cluster being represented by a wide range of pharmaceuticals and natural products.[9,10,11] Amongst the sulfur-containing and nitrogen-containing commercialized hepatoprotector drugs, a special reference should be made to malotilate,[12] SAM,[13] thiotriazolin,[14] thioctic acid and taurine.[15,16]Another innovative cluster of drugs is represented by metal complexes generated based on a concept of modeling the metal-enzyme interaction sites, in where interactions often involve metal-thiolate or metal-amine bonds.[17]. The tested compound is comparable, in terms of its activity to the hepatoprotective drug SAM according to the in vivo and in vitro experiments such as animal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretory function, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liver antitoxic function (the latter has been determined based on the results of a hexobarbital control experiment).

Results

Conclusion