cyclohexyl ketone inhibitors of pin1 dock in a trans-diaxial cyclohexane conformation环己基酮抑制剂trans-diaxial pin1码头的环己烷构象.pdfVIP

Cyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans- Diaxial Cyclohexane Conformation Guoyan G. Xu, Carla Slebodnick, Felicia A. Etzkorn* Department of Chemistry, Virginia Tech, Blacksburg, Virginia, United States of America Abstract Cyclohexyl ketone substrate analogue inhibitors (Ac–pSer-Y[C = OCH]-Pip–tryptamine) of Pin1, the cell cycle regulatory peptidyl-prolyl isomerase (PPIase), were designed and synthesized as potential electrophilic acceptors for the Pin1 active site Cys113 nucleophile to test a proposed nucleophilic addition-isomerization mechanism. Because they were weak inhibitors, models of all three stereoisomers were docked into the active site of Pin1. Each isomer consistently minimized to a trans-diaxial cyclohexane conformation. From this, we hypothesize that Pin1 stretches substrates into a trans-pyrrolidine conformation to lower the barrier to isomerization. Our reduced amide inhibitor of Pin1 adopted a similar trans-pyrrolidine conformation in the crystal structure. The molecular model of 1, which mimics the L-Ser-L-Pro stereochemistry, in the Pin1 ˚ active site showed a distance of 4.4 A, and an angle of 31u between Cys113-S and the ketone carbon. The computational models suggest that the mechanism of Pin1 PPIase is not likely to proceed through nucleophilic addition. Citation: Xu GG, Slebodnick C, Etzkorn FA (2012) Cyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans-Diaxial Cyclohexane Conformation. PLoS ONE 7(9): e44226. doi:10.1371/journal.pone.0044226 Editor: Joseph J. Barchi, National Cancer Institute at Frederick, United States of America Received May 23, 2012; Accepted August 3, 2012; Published September 19, 2012 Copyrigh