Computational structural studies of SGLT2-related polypharmacy
Abstract
INTRODUCTION: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport.
METHODS: The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events.
RESULTS: The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i…
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