Computational binding mechanism of Mycobacterium tuberculosis UDP-NAG enolpyruvyl transferase (MurA) with inhibitors fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic aci

C M Anuradha,C Rajasekhar,Suresh Kumar Chitta,M Chaitanaya,B Babajan

doi:10.1038/npre.2009.3731.1

Abstract

AbstractWorldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and about two million deaths are attributable to TB annually. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structural model of Mtb-MurA enzyme has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. substrate binding pocket, and common docking site. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E.coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structural model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5-sulfonoxyanthranilic acid derivatives is showed best interaction compared with other inhibitor, taking in to this we also design a new efficient analogs of T6361 and T6362 which are showed even better interaction with Mtb-MurA than the parental5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing of a more specific inhibitor for Mtb-MurA enzyme

Highlights

Tuberculosis (TB) is a contagious disease with comparatively high mortality worldwide
Molecular docking study was performed on this 3D structural model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5sulfonoxyanthranilic acid derivatives is showed best interaction compared with other inhibitor, taking in to this we design a new efficient analogs of T6361 and T6362 which are showed even better interaction with Mycobacterium tuberculosis (Mtb)-MurA than the parental5-sulfonoxy-anthranilic acid derivatives
Mtb-MurA using blast-P with PDB selected as database at NCBI, which showed indication of three PDB ID: 1A2N, 1UAE and 1NAW which showed highest homology based on e-value

Summary

Introduction

Tuberculosis (TB) is a contagious disease with comparatively high mortality worldwide. The statistics shows that around three million people throughout the world die annually from tuberculosis [1,2] and that there are around eight million new cases each year, out of which developing countries have a major share [3]. About one third of the world’s population harbors a dormant Mycobacterium tuberculosis (Mtb) infection, representing a significant reservoir of disease for the future. The Bacille Calmette-Guérin (BCG) vaccine is the only available vaccine used against TB world-wide. There is a profound need for the identification and development of novel anti-tuberculosis drugs, which will be active against Mtb. there is a profound need for the identification and development of novel anti-tuberculosis drugs, which will be active against Mtb These compounds should have an ability to penetrate the mycobacterium cell wall, and be active in both the acute and the chronic growth phases

Methods

Results

Conclusion