An overview on crystal structures of InhA protein: Apo-form, in complex with its natural ligands and inhibitors

The enoyl-ACP reductase InhA from the mycobacterial fatty acid biosynthesis pathway has become a target of interest for the development of new anti-tubercular drugs. This protein has been identified as essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis, and...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2018-02, Vol.146, p.318-343
Main Authors: Chollet, Aurélien, Maveyraud, Laurent, Lherbet, Christian, Bernardes-Génisson, Vania
Format: Article
Language:English
Subjects:
Anti-tubercular agents
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Biological Products - chemistry
Biological Products - pharmacology
Chemical Sciences
Coordination chemistry
Crystallographic structures
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug design
Enoyl-ACP-Reductase
InhA
Inhibitors
Ligands
Models, Molecular
Molecular mechanism
Molecular Structure
Oxidoreductases - antagonists & inhibitors
Oxidoreductases - chemistry
Oxidoreductases - metabolism
Structure-Activity Relationship
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Summary:The enoyl-ACP reductase InhA from the mycobacterial fatty acid biosynthesis pathway has become a target of interest for the development of new anti-tubercular drugs. This protein has been identified as essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis, and as the main target of two pro-drugs: isoniazid, the frontline anti-tubercular drug, and ethionamide, a second-line medicine. Since most cases of resistance to isoniazid and ethionamide result from mutations in the mycobacterial activating enzyme (KatG for isoniazid and EthA for ethionamide), research of direct InhA inhibitors, avoiding the activation step, has emerged as a promising strategy for combating tuberculosis. Thereby, InhA is drawing much attention and its three-dimensional structure has been particularly studied. A better understanding of key sites of interactions responsible for InhA inhibition arises thus as an essential tool for the rational design of new potent inhibitors. In this paper, we propose an overview of the 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors. We will first discuss structural and mechanistic aspects in order to highlight key features of the protein before delivering thorough inventory of structures of InhA in the presence of synthetic ligands to underline the key interactions implicated in high affinity inhibition. [Display omitted] •InhA inhibitors as a promising strategy for combating tuberculosis.•Overview of 80 wild-type and mutant InhA enzymes crystallized under different forms.•Structural and mechanistic aspects of InhA enzyme.•Key interactions between InhA and ligands implicated in high affinity inhibition.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.01.047