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Impact of Target-Based Drug Design in Anti-bacterial Drug Discovery for the Treatment of Tuberculosis

  • Anju Choorakottayil Pushkaran
  • Raja Biswas
  • C. Gopi MohanEmail author
Chapter
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 27)

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is a major public health concern. According to the 2017 WHO report, global burden of TB infection was 10.4 million people causing the mortality rate of ~1.6 million. The rapid emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is of major concern in anti-TB drug discovery. There are different druggable targets and its pathways involved in the virulence, which include Mtb cell wall, replication and transcription, regulatory, protein synthesis, membrane transport, and energy production which need to be explored for efficient killing of the bacteria. The ability of the tubercle bacilli to remain within the host intracellular compartment is of other major concern in TB therapy. Thus, to tackle the TB drug resistance, potent inhibitors with novel mechanism of action of different Mtb druggable targets need to be discovered. Three-dimensional structure of different Mtb target was solved for structure-based drug design. The current chapter focuses on some of the key druggable targets in Mtb and also the recent advances in target-based drug designing in the area of anti-tubercular drug discovery.

Keywords

Mycobacterium tuberculosis TB therapy Drug targets Structural biology Chemoinformatics Drug resistance 

Abbreviations

3D

Three-dimensional

ag85

Antigen 85

AMPK

5′adenosine monophosphate-activated protein kinase

AspS

Aspartyl tRNA synthetase

BCG

Bacille Calmette-Guérin

ClpP

Caseinolytic peptidase P

CmaA1

Cyclopropane synthase

d-Ala

d-Alanine

d-Glu

d-Glutamic acid

DprE1

Decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase

FtsZ

Filamenting temperature-sensitive protein Z

GlcB

Malate synthase

GlcNAc

N-acetylglucosamine

GyrB

DNA gyrase subunit B

HTS

High-throughput screening

l-Ala

l-Alanine

Ldt

l,d-transpeptidase

LeuRS

Leucyl-tRNA synthetase

l-Lys

l-Lysine

Lpd

Lipoamide dehydrogenase

MDR

Multidrug-resistant

MEPS

Molecular electrostatic potential surface

meso-DAP

meso-diaminopimelic acid

MIC

Minimum inhibitory concentration

MSA

Multiple sequence alignment

Mtb

Mycobacterium tuberculosis

MurNGlyc

N-glycolylmuramic acid

NMR

Nuclear magnetic resonance

PDB

Protein data bank

PDF

Peptide deformylase

PG

Peptidoglycan

PtpA

Tyrosine phosphatase A

PtpB

Tyrosine phosphatase B

Qcrb

Cytochrome bc1 complex

QSAR

Quantitative structure activity relationship

RNAP

RNA polymerase enzyme

ROS

Reactive oxygen species

TB

Tuberculosis

TCA

Tricarboxylic acid

VS

Virtual screening

WHO

World Health Organization

XDR

Extensively drug-resistant

Notes

Acknowledgements

The author ACP acknowledges Kerala State Council for Science, Technology & Environment (KSCSTE) for awarding Junior Research Fellowship (Grant No:1132/2013/KSCSTE), India. The authors thank Indian Council for Medical Research (ICMR) and Department of Biotechnology (DBT; BT/PR5659/MED/29/564/2012), Government of India, New Delhi, India, for financial support. We also acknowledge gratefully Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, for the infrastructure support.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Anju Choorakottayil Pushkaran
    • 1
  • Raja Biswas
    • 1
  • C. Gopi Mohan
    • 1
    Email author
  1. 1.Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa VidyapeethamKochiIndia

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