Probing multivalency for the inhibition of an enzyme: glycogen phosphorylase as a case study

Abstract

Glycogen phosphorylase is involved in the hepatic glucose production and appears an emerging biological target for the treatment of type 2 diabetes. Two distinct trivalent inhibitors of GP were synthesized either through Cu(I)-assisted 1,3-dipolar cycloaddition or through formation of a tris-oxadiazole derivative. A biological study of the inhibiting properties of these trivalent inhibitors of GP have shown that the valency of the molecules influences slightly the inhibition of the enzyme whereas the presence of a spacer arm between the core and the pharmacophore moieties does not. The possible modes of binding of these multivalent inhibitors to the enzyme are discussed.