{
  "abstract": "Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane-embedded renal transporter and an established therapeutic target for type 2 diabetes. Hyperoside, myricetin, cyanidin-3-O-glucoside and isoliquiritigenin were investigated as a chemically diverse panel of natural scaffolds using a multi-scale computational workflow combining redocking-validated molecular docking, reconstruction of an unresolved transporter segment, molecular dynamics (MD) in an explicit POPC bilayer, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, principal component and free-energy landscape analyses and density functional theory (DFT). The membrane simulations preserved the global hSGLT2 fold while revealing distinct ligand-dependent binding behaviours. Myricetin and cyanidin-3-O-glucoside exhibited limited positional deviations; hyperoside achieved persistent accommodation following an initial adjustment, whereas isoliquiritigenin underwent a marked late rearrangement. Ensemble-based energetic analysis prioritized cyanidin-3-O-glucoside, while hyperoside and myricetin formed an energetically comparable intermediate group and isoliquiritigenin displayed the least favourable profile. Electronic-structure analysis further characterized cyanidin-3-O-glucoside as the most responsive ligand within the DFT subset. Collectively, these findings indicate that glycone-assisted polar anchoring, aromatic complementarity and restricted conformational flexibility promote persistent hSGLT2 recognition. Direct hSGLT2 inhibition and hSGLT1 counter-screening assays remain necessary to establish potency and selectivity.",
  "abstract_shown": true,
  "affiliations": [
    "University Mohammed Premier, Faculty of Science, Laboratory of Applied Chemistry and Environment (LCAE) 1 , Oujda, 60000 Morocco",
    "Laboratoires TBC, Laboratory of Pharmacology, Pharmacokinetics, and Clinical Pharmacy, Faculty of Pharmaceutical and Biological Sciences 2 , Lille, France",
    "Laboratoire d'Amélioration des Productions Agricoles, Biotechnologie et Environnement (LAPABE), Faculté des Sciences, Université Mohammed Premier 3 , Oujda 60000, Morocco",
    "Biology Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU) 4 , Riyadh, 11623, Saudi Arabia"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Oussama Khibech",
      "orcid": "0009-0007-9407-7576"
    },
    {
      "affs": [
        0
      ],
      "name": "Said Abadi"
    },
    {
      "affs": [
        1
      ],
      "name": "Mohamed Bouhrim"
    },
    {
      "affs": [
        2
      ],
      "name": "Yousra Hammouti"
    },
    {
      "affs": [
        0
      ],
      "name": "Mohammed Merzouki"
    },
    {
      "affs": [
        2
      ],
      "name": "Mohamed Addi"
    },
    {
      "affs": [
        3
      ],
      "name": "Mohammed AL-Zharani"
    },
    {
      "affs": [
        3
      ],
      "name": "Fahd A. Nasr"
    },
    {
      "affs": [
        3
      ],
      "name": "Ashraf Ahmed Qurtam"
    },
    {
      "affs": [
        0
      ],
      "name": "Allal Challioui"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8tchv0xwnrm1k.bib",
  "cited_by": 0,
  "doi": "10.1098/rsos.261760",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13730638/?tool=EBI",
  "id": "8tchv0xwnrm1k",
  "issns": [
    "2054-5703"
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  "landing_url": "https://royalsocietypublishing.org/rsos/article/13/11/261760/484006/Design-principles-for-natural-SGLT2-modulators",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Chemistry"
    ],
    [
      "heading",
      "Computational Chemistry"
    ],
    [
      "heading",
      "Computer Modelling and Simulation"
    ],
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7225163277",
  "pdf_url": "https://royalsocietypublishing.org/rsos/article-pdf/doi/10.1098/rsos.261760/6175181/rsos.261760.pdf",
  "pmcid": "PMC13730638",
  "pmid": "42979399",
  "published": "2026-11-04",
  "publisher": "The Royal Society",
  "ris": "https://research.draconitic.com/paper/8tchv0xwnrm1k.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:20:47Z",
      "native_id": "10.1098/rsos.261760",
      "source": "crossref",
      "url": "https://royalsocietypublishing.org/rsos/article/13/11/261760/484006/Design-principles-for-natural-SGLT2-modulators"
    },
    {
      "first_seen": "2026-11-04T15:20:46Z",
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      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13730638"
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    {
      "first_seen": "2026-11-07T12:23:09Z",
      "native_id": "PMC13730638",
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      "url": "https://doi.org/10.1098/rsos.261760"
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  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Biochemistry",
      "subfield": "general"
    },
    {
      "field": "chemistry",
      "origin": "heading:Computational Chemistry",
      "subfield": "theoretical"
    }
  ],
  "title": "Design principles for natural SGLT2 modulators from multi-scale computation",
  "title_text": "Design principles for natural SGLT2 modulators from multi-scale computation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:23:09Z",
  "url": "https://research.draconitic.com/paper/8tchv0xwnrm1k",
  "venue": "Royal Society Open Science",
  "versions": []
}