Flavanones: A potential natural inhibitor of the ATP binding site of PknG of<i>Mycobacterium tuberculosis</i>

Swain, Supriya P; Gupta, Subhi; Das, Nidhi; França, Tanos C. C.; Gonçalves, Arlan da Silva; Ramalho, Teodorico C.; Subrahmanya, Shreya; Narsaria, Utkarsh; Deb, Debashrito; Mishra, Neelam

doi:10.1080/07391102.2021.1965913

Cited by 5 publications

(6 citation statements)

References 66 publications

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“…Like other bacterial pathogens, M. tuberculosis have evolved to secrete effector proteins, including an effector kinase, PknG, to counteract host defense and promote infection (Walburger et al, 2004;Nicholson and Champion, 2022). The kinase activity of PknG is essential to M. tuberculosis pathogenicity (Walburger et al, 2004) and has therefore been a potential antibiotic target for tuberculosis treatments (Gil et al, 2013;Swain et al, 2021). Studies in PknG's role in pathogenesis show that this effector contains versatile activities, such as E3-ubiquitin ligase activity for host protein ubiquitination Shariq et al, 2022) and regulatory activity for metabolism, virulence, and stress response within M. tuberculosis (Khan et al, 2017;Rieck et al, 2017;Lima et al, 2021).…”

Section: Mycobacterium Pkng Phosphorylates Host Tbc1d4 To Prevent Aut...mentioning

confidence: 99%

Bacterial effector kinases and strategies to identify their target host substrates

Louis

Quagliato²,

Lee³

2023

Front. Microbiol.

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Post-translational modifications (PTMs) are critical in regulating protein function by altering chemical characteristics of proteins. Phosphorylation is an integral PTM, catalyzed by kinases and reversibly removed by phosphatases, that modulates many cellular processes in response to stimuli in all living organisms. Consequently, bacterial pathogens have evolved to secrete effectors capable of manipulating host phosphorylation pathways as a common infection strategy. Given the importance of protein phosphorylation in infection, recent advances in sequence and structural homology search have significantly expanded the discovery of a multitude of bacterial effectors with kinase activity in pathogenic bacteria. Although challenges exist due to complexity of phosphorylation networks in host cells and transient interactions between kinases and substrates, approaches are continuously being developed and applied to identify bacterial effector kinases and their host substrates. In this review, we illustrate the importance of exploiting phosphorylation in host cells by bacterial pathogens via the action of effector kinases and how these effector kinases contribute to virulence through the manipulation of diverse host signaling pathways. We also highlight recent developments in the identification of bacterial effector kinases and a variety of techniques to characterize kinase-substrate interactions in host cells. Identification of host substrates provides new insights for regulation of host signaling during microbial infection and may serve as foundation for developing interventions to treat infection by blocking the activity of secreted effector kinases.

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Section: Mycobacterium Pkng Phosphorylates Host Tbc1d4 To Prevent Aut...mentioning

confidence: 99%

Bacterial effector kinases and strategies to identify their target host substrates

Louis

Quagliato²,

Lee³

2023

Front. Microbiol.

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“… 18 Using a similar approach, 477 flavanones from PubChem were docked against the PknG obtaining 6 potential inhibitors. 19 In these last two cases, there was no verification of the potential inhibitors employing biochemical tests. Remarkably, a hybrid approach by pharmacophore-based virtual screening and in vitro studies resulted in the proposal of the validated compound NRB04248.…”

Section: Introductionmentioning

confidence: 97%

“…From a computational point of view, 84 secondary metabolites from medicinal plants (Pelargonium reniforme and Pelargonium sidoides) were studied by molecular docking-based virtual screening achieving 10 potential inhibitors with favorable energy affinities . Using a similar approach, 477 flavanones from PubChem were docked against the PknG obtaining 6 potential inhibitors . In these last two cases, there was no verification of the potential inhibitors employing biochemical tests.…”

Section: Introductionmentioning

confidence: 99%

Identifying RO9021 as a Potential Inhibitor of PknG fromMycobacterium tuberculosis: Combinative Computational and In Vitro Studies

et al. 2022

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Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis ( Mtb ). Despite being considered curable and preventable, the increase of antibiotic resistance is becoming a serious public health problem. Mtb is a pathogen capable of surviving in macrophages, causing long-term latent infection where the mycobacterial serine/threonine protein kinase G (PknG) plays a protective role. Therefore, PknG is an important inhibitory target to prevent Mtb from entering the latency stage. In this study, we use a pharmacophore-based virtual screening and biochemical assays to identify the compound RO9021 (CHEMBL3237561) as a PknG inhibitor. In detail, 1.5 million molecules were screened using a scalable cloud-based setup, identifying 689 candidates, which were further subjected to additional screening employing molecular docking. Molecular docking spotted 62 compounds with estimated binding affinities of −7.54 kcal/mol (s.d. = 0.77 kcal/mol). Finally, 14 compounds were selected for in vitro experiments considering previously reported biological activities and commercial availability. In vitro assays of PknG activity showed that RO9021 inhibits the kinase activity similarly to AX20017, a known inhibitor. The inhibitory effect was found to be dose dependent with a relative IC 50 value of 4.4 ± 1.1 μM. Molecular dynamics simulations predicted that the PknG-RO9021 complex is stable along the tested timescale. Altogether, our study indicates that RO9021 is a noteworthy drug candidate for further developing new anti-TB drugs that hold excellent reported pharmacokinetic parameters.

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“…Another important characteristic of botanical insecticides is their multispecific action, which makes it more difficult for pests to develop resistance to the compound, as opposed to chemical pesticides, which regularly target a specific molecule [ 16 ]. For example, flavanones were evaluated in terms of Mycobacterium tuberculosis viability to act against protein kinase G (PknG) as a new promising drug target [ 17 ], and fukugetin, a natural flavone as an inhibitor of human tissue kallikreins [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

The Potential of Magnolia spp. in the Production of Alternative Pest Control Substances

Hernandez-Rocha

Vásquez-Morales

2023

Molecules

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The irrational use of synthetic pesticides in agriculture has had negative impacts on ecosystems and contributed to environmental pollution. Botanical pesticides offer a clean biotechnological alternative to meet the agricultural challenges posed by pests and arthropods. This article proposes the use of fruit structures (fruit, peel, seed, and sarcotesta) of several Magnolia species as biopesticides. The potential of extracts, essential oils, and secondary metabolites of these structures for pest control is described. From 11 Magnolia species, 277 natural compounds were obtained, 68.7% of which were terpenoids, phenolic compounds, and alkaloids. Finally, the importance of a correct management of Magnolia species to ensure their sustainable use and conservation is stressed.

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Flavanones: A potential natural inhibitor of the ATP binding site of PknG ofMycobacterium tuberculosis

Cited by 5 publications

References 66 publications

Bacterial effector kinases and strategies to identify their target host substrates

Bacterial effector kinases and strategies to identify their target host substrates

Identifying RO9021 as a Potential Inhibitor of PknG fromMycobacterium tuberculosis: Combinative Computational and In Vitro Studies

The Potential of Magnolia spp. in the Production of Alternative Pest Control Substances

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