#1838 SGLT2 computational structural studies investigating polypharmacy

Abstract

Abstract Background and Aims 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 will be prescribed these compounds resulting in 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. Method 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 empaglifozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The centroid of a 5 nanosecond GROMACS molecular dynamics (MD) equilibration was used for docking studies using PLANTS. A bespoke tool was used to identify compounds interacting with key protein residues. CHARM-GUI and bespoke software were used to prepare membrane-bound systems to run in GROMACS using GPU's 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 in the inward-open conformation obtained showed good agreement with published structures. Existing SGLT2i (empaglifozin, dapaglifozin, canaglifozin, ertuglifozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions might provide competitive inhibition for SGLT2i compounds currently used. The compounds identified have no hitherto recognised interactions with SGLT2i; nor do they result in adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.