 |
PDBsum entry 2qgb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hormone/growth factor
|
PDB id
|
|
|
|
2qgb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Biochemical and structural evaluation of highly selective 2-Arylbenzoxazole-Based transthyretin amyloidogenesis inhibitors.
|
|
|
Authors
|
|
S.M.Johnson,
S.Connelly,
I.A.Wilson,
J.W.Kelly.
|
|
|
Ref.
|
|
J Med Chem, 2008,
51,
260-270.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also
display high binding selectivity in blood, it proves useful to systematically
optimize each of the three substructural elements that comprise a typical
inhibitor: the two aryl rings and the linker joining them. In the first study,
described herein, structural modifications to one aryl ring were evaluated by
screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl
substituents on the 2-aryl ring. Several potent and highly selective
amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone
nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5
A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to
characterize their binding orientation. Collectively, the results demonstrate
that thyroid hormone-like substitution patterns on one aryl ring lead to potent
and highly selective TTR amyloidogenesis inhibitors that lack undesirable
thyroid hormone receptor or COX-1 binding.
|
|
|
|
|
|
|
