Nuclear magnetic resonance fragment-based identification of novel FKBP12 inhibitors.
Peptidyl-prolyl cis-trans isomerases are a group of cytosolic enzymes initially characterized by their ability to catalyze the cis-trans isomerization of peptidyl-prolyl bonds. This represents a significant event for protein folding because cis-proline introduces critical bends within the protein conformation. FK506-binding proteins (FKBPs) represent one of the three families of enzymes sharing peptidyl-prolyl cis-trans isomerase activity. Inhibitors of FKBP12, in particular, have potent neurotrophic properties both in vivo and in vitro. Here, we describe a fragment-based unbiased nuclear magnetic resonance drug discovery approach for the identification of novel classes of chemical inhibitors against FKBP12. Compared to FK506, the fragment-based FKBP12 inhibitors developed herein possess significant advantages as drug candidates.
Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, and University of California at San Diego, Division of Biological Sciences, 9500 Gilman Drive, La Jolla, California 92093, USA.
John L
JL
Stebbins
Ziming
Z
Zhang
Jinhua
J
Chen
Bainan
B
Wu
Aras
A
Emdadi
Megan E
ME
Williams
John
J
Cashman
Maurizio
M
Pellecchia
D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry
D009025:Morpholines; D011994:Recombinant Proteins; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus