Unique binding mode of Evogliptin with human dipeptidyl peptidase IV

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Evogliptin ((<I>R</I>)-4-((<I>R</I>)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(<I>tert-</I>butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (<I>S,R</I> diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S<SUB>1</SUB> pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S<SUB>2</SUB> extensive subsite, and that the multiple hydrogen bonds made by the (<I>R</I>)-β-amine group in the S<SUB>2</SUB> pocket and the contacts made by the (<I>R</I>)-<I>tert</I>-butyl group with Arg125 contribute to the high potency observed for Evogliptin.</P>