Inhibition of Mycobacterium tuberculosis MtrA response regulator by anticancer drugs via computational methods

Abstract

Mycobacterium tuberculosis (MTB) causes TB disease and millions of deaths are reported every year. Drug resistance TB and its complex treatment is a big problem worldwide. The present  study aimed to design new and safer antitubercular compounds to tackle this serious threat. The unique drug target is the MtrAB Two-component regulatory system (2CRS) of mycobacteria. MtrAB system consists of MtrB sensor kinase (SK) and MtrA response regulator (RR). This system is essential in MTB and is involved in mycobacteria's proliferation. This important physiological process is operated by the phosphorylation of MtrB and then to MtrA. The phosphorylation mechanism triggers modulation in the expression of MtrA targets genes and helps perform appropriate function. This phenomenon depends on the active and inactive confirmation of MtrA, which involves a ligand (Metal ion complex e.g. Mg2+). In this study, anti-cancerous compounds were selected for the inhibition of MtrA. However, molecular docking exhibited binding affinity ranging from −10.8 to −4.7 kcal/mol, targeting the binding pocket of the selected Tuberculosis–MtrA protein (PDB ID: 5L8X). This energy difference between the native ligand and docked compounds showed that the six molecules: (Risperidone, 2-(benzofuran-2-yl)-6,7-dimethyl-4H-chromen-4-one, (2E)-1-(4-hydroxyphenyl)-3-(quinolin-4-yl)prop-2-en-1-one, Estradiol Cypionate, (2Z)-6-hydroxy-2-(3,4,5-trimethoxybenzylidene)-1-benzofuran-3(2H)-one, (2E)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-(3-hydroxyphenyl)prop-2-en-1-one) mentioned are more potent than the native ligand.These six molecules were first time reported as the inhibitor for MtrA of MtrAB Two-component regulatory system and can be utelize for further study.