Design principles for natural SGLT2 modulators from multi-scale computation
4 affiliations
- 1University Mohammed Premier, Faculty of Science, Laboratory of Applied Chemistry and Environment (LCAE) 1 , Oujda, 60000 Morocco
- 2Laboratoires TBC, Laboratory of Pharmacology, Pharmacokinetics, and Clinical Pharmacy, Faculty of Pharmaceutical and Biological Sciences 2 , Lille, France
- 3Laboratoire d'Amélioration des Productions Agricoles, Biotechnologie et Environnement (LAPABE), Faculté des Sciences, Université Mohammed Premier 3 , Oujda 60000, Morocco
- 4Biology Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU) 4 , Riyadh, 11623, Saudi Arabia
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.
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BibTeX
@article{khibech2026design,
title = {{Design principles for natural SGLT2 modulators from multi-scale computation}},
author = {Oussama Khibech and Said Abadi and Mohamed Bouhrim and Yousra Hammouti and Mohammed Merzouki and Mohamed Addi and Mohammed AL-Zharani and Fahd A. Nasr and Ashraf Ahmed Qurtam and Allal Challioui},
journal = {Royal Society Open Science},
year = {2026},
month = nov,
doi = {10.1098/rsos.261760},
url = {https://royalsocietypublishing.org/rsos/article/13/11/261760/484006/Design-principles-for-natural-SGLT2-modulators},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design principles for natural SGLT2 modulators from multi-scale computation
AU - Oussama Khibech
AU - Said Abadi
AU - Mohamed Bouhrim
AU - Yousra Hammouti
AU - Mohammed Merzouki
AU - Mohamed Addi
AU - Mohammed AL-Zharani
AU - Fahd A. Nasr
AU - Ashraf Ahmed Qurtam
AU - Allal Challioui
PY - 2026
DA - 2026/11/04
JO - Royal Society Open Science
DO - 10.1098/rsos.261760
UR - https://royalsocietypublishing.org/rsos/article/13/11/261760/484006/Design-principles-for-natural-SGLT2-modulators
AB - 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.
SN - 2054-5703
ER -