Advances in Computational Studies of Potential Drug Targets in Mycobacterium tuberculosis

Tuberculosis continues to remain as one of the leading causes of death worldwide, in spite of significant progress being made in the last twenty years through increased compliance to treatment. The current review gives an overview of the recent efforts made in the endeavor to identify novel inhibitors and promising drug targets for Mycobacterium tuberculosis with structure and ligand-based approaches along with bioinformatics studies following complete sequencing of its genome. A large number of these studies target biomolecules in metabolic pathways that are vital for the survival of the microorganism. A discussion on efforts to study metalloproteins as relatively underexplored targets in the context of their druggability is also presented.

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Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis

Biochemical Journal ◽

10.1042/bj20110002 ◽

2011 ◽

Vol 436 (3) ◽

pp. 729-739 ◽

Cited By ~ 23

Author(s):

Marcio V. B. Dias ◽

William C. Snee ◽

Karen M. Bromfield ◽

Richard J. Payne ◽

Satheesh K. Palaninathan ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Structural Investigation ◽

Catalytic Mechanism ◽

Shikimate Pathway ◽

Structural Rearrangement ◽

Competitive Inhibitors ◽

Structural Insights ◽

Potential Drug Targets

The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19–24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

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Generation and Analysis of Large-Scale Data-Driven Mycobacterium tuberculosis Functional Networks for Drug Target Identification

Advances in Bioinformatics ◽

10.1155/2011/801478 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 15

Author(s):

Gaston K. Mazandu ◽

Nicola J. Mulder

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Large Scale ◽

Global Analysis ◽

Interaction Network ◽

Interaction Networks ◽

Microbial Pathogens ◽

Potential Drug ◽

Functional Interaction ◽

Potential Drug Targets

Technological developments in large-scale biological experiments, coupled with bioinformatics tools, have opened the doors to computational approaches for the global analysis of whole genomes. This has provided the opportunity to look at genes within their context in the cell. The integration of vast amounts of data generated by these technologies provides a strategy for identifying potential drug targets within microbial pathogens, the causative agents of infectious diseases. As proteins are druggable targets, functional interaction networks between proteins are used to identify proteins essential to the survival, growth, and virulence of these microbial pathogens. Here we have integrated functional genomics data to generate functional interaction networks between Mycobacterium tuberculosis proteins and carried out computational analyses to dissect the functional interaction network produced for identifying drug targets using network topological properties. This study has provided the opportunity to expand the range of potential drug targets and to move towards optimal target-based strategies.

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Mycobacterium tuberculosis H37Rv: In Silico Drug Targets Identification by Metabolic Pathways Analysis

International Journal of Evolutionary Biology ◽

10.1155/2014/284170 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Asad Amir ◽

Khyati Rana ◽

Arvind Arya ◽

Neelesh Kapoor ◽

Hirdesh Kumar ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

In Silico ◽

Metabolic Pathways ◽

Drug Targets ◽

Pathogenic Bacteria ◽

Homo Sapiens ◽

Protein Sequences ◽

Mycobacterium Tuberculosis H37rv ◽

Drug Molecules ◽

Pathways Analysis

Mycobacterium tuberculosis (Mtb) is a pathogenic bacteria species in the genus Mycobacterium and the causative agent of most cases of tuberculosis. Tuberculosis (TB) is the leading cause of death in the world from a bacterial infectious disease. This antibiotic resistance strain lead to development of the new antibiotics or drug molecules which can kill or suppress the growth of Mycobacterium tuberculosis. We have performed an in silico comparative analysis of metabolic pathways of the host Homo sapiens and the pathogen Mycobacterium tuberculosis (H37Rv). Novel efforts in developing drugs that target the intracellular metabolism of M. tuberculosis often focus on metabolic pathways that are specific to M. tuberculosis. We have identified five unique pathways for Mycobacterium tuberculosis having a number of 60 enzymes, which are nonhomologous to Homo sapiens protein sequences, and among them there were 55 enzymes, which are nonhomologous to Homo sapiens protein sequences. These enzymes were also found to be essential for survival of the Mycobacterium tuberculosis according to the DEG database. Further, the functional analysis using Uniprot showed involvement of all the unique enzymes in the different cellular components.

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Protein Integrated Network Analysis to Reveal Potential Drug Targets Against Extended Drug-Resistant Mycobacterium tuberculosis XDR1219

Molecular Biotechnology ◽

10.1007/s12033-021-00377-w ◽

2021 ◽

Author(s):

Noor ul Ain Zahra ◽

Faiza Jamil ◽

Reaz Uddin

Keyword(s):

Mycobacterium Tuberculosis ◽

Network Analysis ◽

Drug Targets ◽

Drug Resistant ◽

Potential Drug ◽

Integrated Network ◽

Potential Drug Targets

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Strategies to Control Human Lymphatic Filarial Infection: Tweaking Host’s Immune System

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190618110613 ◽

2019 ◽

Vol 19 (14) ◽

pp. 1226-1240 ◽

Cited By ~ 2

Author(s):

Puvvada Kalpana Murthy

Keyword(s):

Drug Targets ◽

Parasitic Infection ◽

Wuchereria Bancrofti ◽

Immune Competence ◽

Potential Drug ◽

Filarial Infection ◽

Alternative Strategies ◽

Vaccine Candidates ◽

Potential Drug Targets ◽

Made In

Human lymphatic filariasis (LF), a parasitic infection caused by the nematodes Wuchereria bancrofti, Brugia malayi and B. timori, and transmitted by mosquito, results in a debilitating disease commonly identified as ‘elephantiasis’. LF affects millions of people in India and several other tropical and sub-tropical countries imposing a huge economic burden on governments due to disability associated loss of man-hours and for disease management. Efforts to control the infection by WHO’s mass drug administration (MDA) strategy using three antifilarials diethylcarbamazine, albendazole and ivermectin are only partly successful and therefore, there is an immediate need for alternative strategies. Some of the alternative strategies being explored in laboratories are: enhancing the immune competence of host by immunomodulation, combining immunomodulation with antifilarials, identifying immunoprophylactic parasite molecules (vaccine candidates) and identifying parasite molecules that can be potential drug targets. This review focuses on the advances made in this direction.

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