2qgd | pdb_00002qgd
Human transthyretin (TTR) complexed with 2-(3,5-Dibromo-4-hydroxyphenyl)benzoxazole
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Overview
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.
About this Structure
2QGD is a Single protein structure of sequence from Homo sapiens with MR5 as ligand. Known structural/functional Sites: AC1 and AC2. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Wed Feb 13 08:14:28 2008
