title: Cyclohexyl ketone inhibitors of Pin1 dock in a trans-diaxial cyclohexane conformation.
abstract: Cyclohexyl ketone substrate analogue inhibitors (Ac-pSer-Ψ[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 Å, and an angle of 31° 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.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Guoyan G
authors.initials: GG
authors.lastname: Xu
authors.forename: Carla
authors.initials: C
authors.lastname: Slebodnick
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Etzkorn
mesh_terms: D003510:Cyclohexanes / Q000737:chemistry*; D007659:Ketones / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D003510:Cyclohexanes; D007659:Ketones; D019696:Peptidylprolyl Isomerase