title: Modulation of the fibrillogenesis inhibition properties of two transthyretin ligands by halogenation.
abstract: The 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; C-I...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.
authors.affiliation: Laboratory of Biochemistry, Bioengineering Department, Institut Químic de Sarrià, Universitat Ramon Llull , ‡Pharmacoinformatics Group, Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute)-Universitat Pompeu Fabra , §Institut de Química Avançada de Catalunya (IQAC-CSIC), ⊥Drug Discovery Platform, Parc Científic de Barcelona , Barcelona, Spain.
authors.forename: Ellen Y
authors.initials: EY
authors.lastname: Cotrina
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.forename: Lluís
authors.initials: L
authors.lastname: Bosch
authors.forename: Marta
authors.initials: M
authors.lastname: Vilà
authors.forename: Daniel
authors.initials: D
authors.lastname: Blasi
authors.forename: Jordi
authors.initials: J
authors.lastname: Quintana
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
authors.forename: Gemma
authors.initials: G
authors.lastname: Arsequell
authors.forename: Antoni
authors.initials: A
authors.lastname: Planas
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valencia
mesh_terms: D004061:Diflunisal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005439:Flufenamic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011228:Prealbumin; D005439:Flufenamic Acid; D004061:Diflunisal