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  1. Article ; Online: Molecular dynamics-derived pharmacophores of Schistosoma glutathione transferase in complex with bromosulfophthalein: Screening and analysis of potential inhibitors.

    Valli, Akeel / Achilonu, Ikechukwu

    Journal of molecular graphics & modelling

    2023  Volume 122, Page(s) 108457

    Abstract: Schistosoma glutathione transferases (GSTs) have been identified as attractive drug targets for the design of novel antischistosomals. Here, we used in silico methods to validate the discriminative inhibitory properties of bromosulfophthalein (BSP) ... ...

    Abstract Schistosoma glutathione transferases (GSTs) have been identified as attractive drug targets for the design of novel antischistosomals. Here, we used in silico methods to validate the discriminative inhibitory properties of bromosulfophthalein (BSP) against the 26-kDa GST from S. japonicum (Sj26GST), and the 28-kDa GST from S. haematobium (Sh28GST), versus human GST (hGST) isoforms alpha (hGSTA), mu (hGSTM) and pi (hGSTP). The use of BSP as an archetypal selective inhibitor was harnessed to produce molecular dynamics-derived pharmacophores of the two targets. Pharmacophore-based screening using a large dataset of experimental and approved drug compounds was performed to produce a shortlist of candidates. The top candidate for each target was prioritised via molecular docking, yielding guanosine-3'-monophosphate-5'-diphosphate (G3D) for Sj26GST, and quercetin-3'-O-phosphate (Q3P) for Sh28GST. Comparative molecular dynamics studies of both candidates compared to BSP showed similar characteristics of binding stability and strength, suggesting their potential to emulate the inhibitory effects of BSP.
    MeSH term(s) Animals ; Humans ; Sulfobromophthalein ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Pharmacophore ; Schistosoma/metabolism ; Glutathione Transferase/chemistry ; Glutathione Transferase/metabolism ; Glutathione/metabolism
    Chemical Substances Sulfobromophthalein (0C2P5QKL36) ; Glutathione Transferase (EC 2.5.1.18) ; Glutathione (GAN16C9B8O)
    Language English
    Publishing date 2023-03-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1396450-1
    ISSN 1873-4243 ; 1093-3263
    ISSN (online) 1873-4243
    ISSN 1093-3263
    DOI 10.1016/j.jmgm.2023.108457
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3491: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Comparative structural analysis of the human and Schistosoma glutathione transferase dimer interface using selective binding of bromosulfophthalein.

    Valli, Akeel / Achilonu, Ikechukwu

    Proteins

    2022  Volume 90, Issue 8, Page(s) 1561–1569

    Abstract: The binding channel of Schistosoma glutathione transferase (SGST) has been identified to possess a non-substrate site implicated in enzyme inhibition. This binding channel is formed by the interface of the GST dimer. We produced a comparative ... ...

    Abstract The binding channel of Schistosoma glutathione transferase (SGST) has been identified to possess a non-substrate site implicated in enzyme inhibition. This binding channel is formed by the interface of the GST dimer. We produced a comparative characterization of the SGST dimer interface with respect to that of human GST (hGST) analogues using the selective binding of bromosulfophthalein (BSP). First, two SGST and three hGST structures were used as search queries to assemble a data set of 48 empirical GST structures. Sequence alignment to generate a universal residue indexing scheme was then performed, followed by local superposition of the dimer interface. Principal component analysis revealed appreciable variation of the dimer interface, suggesting the potential for selective inhibition of SGST. BSP was found to dock invariably in the dimer interface core pocket, placing it in proximity to the GST catalytic domains, through which it may exert its inhibitory behavior. Binding poses across the GST forms were distinguished with ligand interaction profiling, where SGST complexes showed stabilization of ligand aromatic- and sulfonate moieties, which altogether anchor the ligand and produce a tight association. In comparison, missing aromatic stabilization in the hGST complexes impart large bonding distances, causing mobile poses likely to dissociate. Altogether, this study illustrates the potential for selective inhibition of SGST, rationalizes the selective behavior of the BSP inhibitor, and produces a reliable metric for construction and validation of pharmacophore models of the SGST binding channel.
    MeSH term(s) Animals ; Binding Sites ; Glutathione Transferase/genetics ; Glutathione Transferase/metabolism ; Humans ; Ligands ; Schistosoma/metabolism ; Sulfobromophthalein/metabolism
    Chemical Substances Ligands ; Sulfobromophthalein (0C2P5QKL36) ; Glutathione Transferase (EC 2.5.1.18)
    Language English
    Publishing date 2022-04-02
    Publishing country United States
    Document type Comparative Study ; Journal Article
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26338
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2291: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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