In silico antitubercular activity analysis of benzofuran and naphthofuran derivatives.

Prashantha Karunakar,Chamarahalli Ramakrishnaiyer Girija,Kunigal Venugopal Shivakumar,Venkatarangaiah Krishna,Venkatappa Krishnamurthy

doi:10.1155/2014/697532

Prashantha Karunakar, Chamarahalli Ramakrishnaiyer Girija + Show 3 more

Open Access

https://doi.org/10.1155/2014/697532

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Abstract

For the human health, Mycobacterium tuberculosis (MTB) is the deadliest enemy since decades due to its multidrug resistant strains. During latent stage of tuberculosis infection, MTB consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Using in silico approach, the molecular docking of benzofuran and naphthofuran derivatives and dynamic study of benzofuran derivative were performed. It was observed that compound Ethyl 5-bromo-3-ethoxycarbonylamino-1-benzofuran-2-carboxylate could be stabilized at the active site for over 10 ns of simulation. Here we suggest that derivatives of benzofuran moiety can lead to developing novel antituberculosis drugs.

Highlights

Furan having various pharmacological and biological activities such as antituberculosis [1], anti-inflammatory [2], and antibacterial [3] activities attracted the attention of synthetic chemists
Mycobacteria can adapt to the host environment by two-component signal transduction system (TCS), where they sense, respond, and adapt to changes in the environment by modulating the expression of subsets of genes in response to specific extracellular signals
The in silico interaction of phosphodonors to NarL was carried out and it was observed that all compounds were binding to active site, though blind docking was performed

Summary

Introduction

Furan having various pharmacological and biological activities such as antituberculosis [1], anti-inflammatory [2], and antibacterial [3] activities attracted the attention of synthetic chemists. NarX is a membrane-bound nitrate sensor [10] and NarL is a cytoplasmic response regulator consisting of N-terminal receiver domain and C-Terminal effector domain. There is 35% overall amino-acid identity between E. coli and MTB NarL and their active sites superimpose exactly and the positions of the active site residues are nearly identical [30]. Based on this sequence homology, NarL has been predicted to be involved in the regulation of anaerobic nitrogen metabolism in MTB (Tuberculist website: http://genolist.pasteur.fr/TubercuList/) and is identified as potential drug target (http://www.uniprot .org/uniprot/O53856). Blocking the active site will inhibit the phosphorylation activity of NarL and negatively affects the MTB adaptation

Materials and Methods

Results and Discussions

OD2 CG OD1