Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.

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Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E

Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.

Protein Sci. 2005 Jul;14(7):1760-71. doi: 10.1110/ps.051432405.

PubMed ID

15987904 [ View in PubMed

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Abstract

Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Adenosine phosphate	Glycogen phosphorylase, liver form	Protein	Humans	Unknown	Activator	Details