Modulation of the Fibrillogenesis Inhibition Properties of Two Transthyretin Ligands by Halogenation
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 obse...
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| Published in: | Journal of medicinal chemistry Vol. 56; no. 22; pp. 9110 - 9121 |
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| Main Authors: | , , , , , , , , , |
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American Chemical Society
27-11-2013
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| 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; 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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| AbstractList | 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. 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; 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. |
| Author | Cotrina, Ellen Y Planas, Antoni Bosch, Lluís Centeno, Nuria B Quintana, Jordi Pinto, Marta Vilà, Marta Valencia, Gregorio Blasi, Daniel Arsequell, Gemma |
| AuthorAffiliation | Institut de Química Avançada de Catalunya (IQAC−CSIC) Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute)-Universitat Pompeu Fabra Drug Discovery Platform 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 Parc Científic de Barcelona |
| AuthorAffiliation_xml | – name: Parc Científic de Barcelona – name: – name: Institut de Química Avançada de Catalunya (IQAC−CSIC) – name: Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute)-Universitat Pompeu Fabra – name: Drug Discovery Platform – name: Pharmacoinformatics Group, Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences – name: Laboratory of Biochemistry, Bioengineering Department – name: Institut Químic de Sarrià, Universitat Ramon Llull |
| Author_xml | – sequence: 1 givenname: Ellen Y surname: Cotrina fullname: Cotrina, Ellen Y – sequence: 2 givenname: Marta surname: Pinto fullname: Pinto, Marta – sequence: 3 givenname: Lluís surname: Bosch fullname: Bosch, Lluís – sequence: 4 givenname: Marta surname: Vilà fullname: Vilà, Marta – sequence: 5 givenname: Daniel surname: Blasi fullname: Blasi, Daniel – sequence: 6 givenname: Jordi surname: Quintana fullname: Quintana, Jordi – sequence: 7 givenname: Nuria B surname: Centeno fullname: Centeno, Nuria B – sequence: 8 givenname: Gemma surname: Arsequell fullname: Arsequell, Gemma – sequence: 9 givenname: Antoni surname: Planas fullname: Planas, Antoni – sequence: 10 givenname: Gregorio surname: Valencia fullname: Valencia, Gregorio email: gregorio.valencia@iqac.csic.es |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24147937$$D View this record in MEDLINE/PubMed |
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| Snippet | The amyloidogenic protein transthyretin (TTR) is thought to aggregate into amyloid fibrils by tetramer dissociation which can be inhibited by a number of small... |
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| SubjectTerms | Diflunisal - chemistry Diflunisal - metabolism Diflunisal - pharmacology Flufenamic Acid - chemistry Flufenamic Acid - metabolism Flufenamic Acid - pharmacology Halogenation Humans Kinetics Ligands Models, Molecular Prealbumin - chemistry Prealbumin - metabolism Protein Multimerization - drug effects Protein Structure, Secondary Structure-Activity Relationship |
| Title | Modulation of the Fibrillogenesis Inhibition Properties of Two Transthyretin Ligands by Halogenation |
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