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|2qge, resolution 1.45Å ()|
|Gene:||TTR, PALB (Homo sapiens)|
Human transthyretin (TTR) complexed with 2-(3,5-Dimethylphenyl)benzoxazole
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.
Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors., Johnson SM, Connelly S, Wilson IA, Kelly JW, J Med Chem. 2008 Jan 24;51(2):260-70. Epub 2007 Dec 21. PMID:18095641
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Johnson SM, Connelly S, Wilson IA, Kelly JW. Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. J Med Chem. 2008 Jan 24;51(2):260-70. Epub 2007 Dec 21. PMID:18095641 doi:10.1021/jm0708735
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