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Modulation of the Fibrillogenesis Inhibition Properties of Two Transthyretin Ligands by Halogenation
journal contribution
posted on 2013-11-27, 00:00 authored by Ellen
Y. Cotrina, Marta Pinto, Lluís Bosch, Marta Vilà, Daniel Blasi, Jordi Quintana, Nuria B. Centeno, Gemma Arsequell, Antoni Planas, Gregorio ValenciaThe
amyloidogenic protein transthyretin (TTR) is thought to aggregate
into amyloid fibrils by tetramer dissociation which can be inhibited
by a number of small molecule compounds. Our analysis of a series
of crystallographic protein-inhibitor complexes has shown no clear
correlation between the observed molecular interactions and the in
vitro activity of the inhibitors. From this analysis, it emerged that
halogen bonding (XB) could be mediating some key interactions. Analysis
of the halogenated derivatives of two well-known TTR inhibitors has
shown that while flufenamic acid affinity for TTR was unchanged by
halogenation, diflunisal gradually improves binding up to 1 order
of magnitude after iodination through interactions that can be interpreted
as a suboptimal XB (carbonyl Thr106: I...O distance 3.96–4.05
Å; CI...O angle 152–156°) or as rather optimized
van der Waals contacts or as a mixture of both. These results illustrate
the potential of halogenation strategies in designing and optimizing
TTR fibrillogenesis inhibitors.
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Transthyretin Ligandssuboptimal XBTTR fibrillogenesis inhibitorsflufenamic acid affinityHalogenationThe amyloidogenic protein transthyretinmolecule compoundsFibrillogenesis Inhibition PropertiesTTR inhibitorsoptimized van der Waals contactsinteractionhalogenation strategiesamyloid fibrilsanalysisI...Otetramer dissociation1 order