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

Chollet, Aurélien; Maveyraud, Laurent; Lherbet, Christian; Bernardes-Génisson, Vânia

doi:10.1016/j.ejmech.2018.01.047

Cited by 49 publications

(49 citation statements)

References 69 publications

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“…It interacts directly with the adjacent subunit, suggesting that the quaternary structure could be involved in the modulation of the MtInhA flexibility. Besides, a detailed structural analysis of all available MtInhA crystal structures corroborated the hypothesis in which the A- and B-loops have lower values of B-factors in relation to the SBL, which faces the outside of the tetramer toward the solvent 18–21 .…”

Section: Introductionsupporting

confidence: 63%

The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

Tarabini

Timmers

Sequeiros-Borja

et al. 2019

Sci Rep

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Flexibility is a feature intimately related to protein function, since conformational changes can be used to describe environmental changes, chemical modifications, protein-protein and protein-ligand interactions. In this study, we have investigated the influence of the quaternary structure of 2-trans-enoyl-ACP (CoA) reductase or InhA, from Mycobacterium tuberculosis, to its flexibility. We carried out classical molecular dynamics simulations using monomeric and tetrameric forms to elucidate the enzyme’s flexibility. Overall, we observed statistically significant differences between conformational ensembles of tertiary and quaternary structures. In addition, the enzyme’s binding site is the most affected region, reinforcing the importance of the quaternary structure to evaluate the binding affinity of small molecules, as well as the effect of single point mutations to InhA protein dynamics.

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Section: Introductionsupporting

confidence: 63%

The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

Tarabini

Timmers

Sequeiros-Borja

et al. 2019

Sci Rep

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“…InhA is one of the key enzymes involved in the synthesis of mycolic acid, which is an important component of Mycobacterium spp. cell walls (37). Thus, InhA may be suggested as a potential antimicrobial target of compound MT.…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative

et al. 2020

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Mostotrin (MT), a novel compound, at least five orders of magnitude more soluble in water than its mother substance, was designed and synthesised from tryptanthrin (TR). Its structure was established by nuclear magnetic resonance and mass spectrometry data and confirmed by X-ray analysis, revealing that MT is a pentacyclic product with an additional pseudo-cycle formed with the participation of one intramolecular hydrogen bond. Antimicrobial activity and cytotoxic action against tumour cells in vitro, as well as anti-tumour effects, acute toxicity and anti-inflammatory activities in vivo, were evaluated. Antimicrobial properties of MT against Mycobacterium spp and Bacillus cereus ATcc 10702 appeared to be the same as that of TR, but against the other strains used it was weaker. Furthermore, MT exhibited 5-10 times higher cytotoxic activities against tumour cell lines HcT-116, МСF-7 and K-562 than TR, but was less toxic than TR (Ld 50 of MT was 375 mg/kg, while Ld 50 for TR was 75 mg/kg). Additionally, compounds MT and TR were studied in dNA binding tests. The quenching of its fluorescence on addition to DNA solution established MT to be capable of binding to dNA. Its anti-tumour action in vivo on mice with the ascitic form of Ehrlich carcinoma was promising, particularly with joint application of MT and the antitumour drug doxorubicin. In this model, the survival and life span for the doxorubicin and 1 co-treatment group were significantly higher compared to doxorubicin treatment alone. The compound MT showed a lower immunosuppressive effect than TR at the early stages of inflammation induced in mice by LPS from E. сoli (MT hardly inhibited the release of IL-1, IL-2, or INF-γ). These results demonstrated that MT is a perspective hit compound for drug development. In our opinion, further evaluation on the biological effects of MT and its synthetic analogues could lead to safer and more effective anti-tumour and anti-tuberculosis agents than TR itself. MT has also the prospect of application in combination with known anti-tumour drugs for the treatment of oncological diseases.

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“…5 The use of INH in the HIV carrying TB patients is also well documented. 6 INH and ETH being prodrugs, must be activated by some enzymes. A bacterial catalase-peroxidase enzyme in Mtb known as KatG activates INH 7 whereas the monooxygenase ethA activates the ETH.…”

Section: Tuberculosis (Tb) a Deadly Infectious Disease Caused By Thementioning

confidence: 99%

Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA

Shaikh

Kanhed

Chandrasekaran

et al. 2019

Bioorganic & Medicinal Chemistry Letters

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InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important firstline drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H 37 Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC 50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.

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

Cited by 49 publications

References 69 publications

The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

The importance of the quaternary structure to represent conformational ensembles of the major Mycobacterium tuberculosis drug target

Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative

Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA

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