Structure-based design of novel human Pin1 inhibitors (II).
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.
Dong
Liming
L
Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
Marakovits
Joseph
J
Hou
Xinjun
X
Guo
Chuangxing
C
Greasley
Samantha
S
Dagostino
Eleanor
E
Ferre
Roseann
R
Johnson
M Catherine
MC
Kraynov
Eugenia
E
Thomson
James
J
Pathak
Ved
V
Murray
Brion W
BW
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
D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase