Molecular modelling, docking and interaction studies of human-plasmogen and salmonella enolase with enolase inhibitors.

Digvijay Singh Chauhan,Sharat Chandra,Tiratha Raj Singh,Arun Gupta

doi:10.6026/97320630008185

Abstract

Salmonella enteric serovar Typhi Ty2 is a human specific pathogen and an etiological agent for typhoid fever. Most of Salmonella serotypes produce glycogen which has a comparatively minor role in virulence and colonization, but has a more significant role in survival. Enzymes present in glycolytic pathway of bacteria help bacteria to survive by activating other factors inside host. Numerous pathogenic bacteria species intervene with the plasminogen system, and this plasminogen–enolase association may play a critical role in the virulence of S. Typhi by causing direct damage to the host cell extracellular matrix, possibly by enzymic degradation of extracellular matrix proteins or other protein constituents. In this study, molecular modelling of enolase of Salmonella has been accomplished in silico by comparative modelling; we have then analyzed Human alpha enolase which is a homodimer and serves on epithelial cells with our model. Both Structures were docked by D-tartronate semialdehyde phosphate (TSP) and 3-aminoenolpyruvate phosphate (AEP) enolase inhibitors. Our study shows that salmonella enolase and human enolase have different active sites in their structure. This will help in development of new ligands, more suitable for inhibiting bacterial survival inside host as vaccines for typhoid fever are not fully protective. The study also confirmed that enolase Salmonella and Human Plasminogen suggested direct physical interaction between both of them as the activation loop of plasminogen residues showed conformational changes similar to the tissue type plasminogen activator. Various computational biology tools were used for our present study such as Modeller, Molegro Virtual Docker, Grommacs.

Highlights

The treatment of typhoid fever is complicated by the emergence of drug resistance
It has been proposed that one function of bacterial plasminogen receptor (PlgR) is to potentiate bacterial damage to and bacterial spread through tissue barriers, such as basement membranes. [9, 10] In vitro tissue culture studies have identified some of the host cell responses that lead to Salmonella entry including actin rearrangement and polymerization at host cell membrane and accumulation of cytoskeleton protein at the site of bacterial entry [11]
In the present study, it has been concluded that α-enolase could mediate the binding of S

Summary

Introduction

Cell-surface protein-mediated interactions are known to play a major role in disease-progression. Structure based comparative analyses of Salmonella enolase and Human alpha enolase was performed in which different active residues and different active pockets in both structures were found. These bacteria immobilize plasminogen on their cell surfaces and enhance the tPA catalyzed plasminogen activation.

Results

Conclusion