title: Structure-based design of novel human Pin1 inhibitors (II).
abstract: Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Joseph
authors.initials: J
authors.lastname: Marakovits
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dagostino
authors.forename: Roseann
authors.initials: R
authors.lastname: Ferre
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Johnson
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.forename: James
authors.initials: J
authors.lastname: Thomson
authors.forename: Ved
authors.initials: V
authors.lastname: Pathak
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase