Computational Strategies to Reactivate Glucose Uptake through Increased GLP-1 Lifetime

Abstract

In type 2 diabetes, high blood sugar leads to hyperinsulinemia, which, over time, causes the body to develop insulin resistance and hyperglycemia. The short-lived peptidic hormone glucagon-like peptide 1 (GLP-1) signals for insulin release. Dipeptidyl peptidase 4 (DPP-4) regulates circulating GLP-1 lifetime through cleavage of the first two N-terminal amino acids. Inhibition of this cleavage clinically leads to reversal of diabetic symptoms but blocks the regulatory function DPP-4 has on other circulating hormone peptides. Selective prolonging of GLP-1 signaling is therefore a desirable area of current research. We probed three different approaches to formulate a drug that solves these problems. Our first approach used ChimeraX to characterize the binding pockets and key interactions of different substances in DPP-4. Pharmacophores that would decrease the activity of the enzyme but not eliminate GLP-1 binding were identified. Our second approach involved aligning different DPP-4 substrates to a short peptide bound to DPP-4 in order to estimate where GLP-1 bound outside the active site. Our results suggest GLP-1 binding may involve sites distinct from many of the other DPP-4 substrates, offering a path towards selective inhibition. Our third approach looked for ways to enhance the binding of GLP-1 to its receptor in the absence of its N-terminal amino acids. Key pharmacophore sites were identified.