How SGLT2 inhibitors interact with metformin? A molecular dynamics study

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a group of drugs that are a staple in diabetes treatment. Its representatives dapagliflozin and empagliflozin are oftentimes used in combination with other antidiabetic drugs such as metformin. In this manuscript, we examine the interactions of dapagliflozin and empagliflozin in mixtures of metformin and water, varying the concentration of metformin to better reflect the drug ratios prescribed in therapy. We found that both SGLT2 inhibitors have a tendency to hydrogen bond with water rather than metformin, with more bonds formed simultaneously that have a lifetime in the picosecond range. These findings were corroborated with structural information, thus providing a backbone for future understanding of transport processes of SGLT2 inhibitors and metformin in highly complex environments.