A molecular dynamics investigation of drug dissociation from SGLT and its implication in antidiabetic medication development

Abstract

As constituents of the sodium-dependent glucose cotransporter (SGLT) family of proteins, both SGLT1 and SGLT2 assume significant physiological functions in the human body. Few research studies have attempted to delve into the unbinding processes that underlie the substrate-binding site of SGLT. In this study, molecular dynamics (MD) simulations of high-resolution X-ray crystal structures revealed the conserved properties of the ligand-binding pockets of SGLT1 and SGLT2. The conserved residues, Phe98, His80, and Glu99, at the SGLT2 substrate binding site contribute to hydrogen bond formation as well as hydrophobic interactions, allowing for the targeted selective inhibition as a result. van der Waals forces have played a crucial role in developing successful medications that block SGLT1/2. Additionally, electrostatic attractions were instrumental in identifying empagliflozin as a potent antidiabetic drug. Our research demonstrated that empagliflozin, ertugliflozin, and LX2761 competed more effectively, whether targeting SGLT1 or SGLT2. The principles of competitive inhibition have been newly understood based on potential mean force (PMF) simulations, where high-affinity inhibitors show route lengths of ∼17.6 Å and ∼17.5 Å from the binding sites to the open state for SGLT1 and SGLT2, respectively. Consequently, we hypothesized that potent antidiabetic agents would tend to bind more deeply within the SGLT1/2 binding site compared to the substrate. In this investigation, a broad pathway was identified, involving the three ligands empagliflozin, ertugliflozin, and LX2761, and the substrate glucose, all being drawn towards an opening between M1b, M2, M6a, and M10 (for SGLT1), as well as TM1b, TM2, TM6a, and TM10 (for SGLT2). This noteworthy observation may significantly contribute to our understanding of drug dissociation mechanisms.