Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma
| Autor: | Afshan Begum, A.E. Sauer-Eriksson, Irina Iakovleva, Lina Nilsson, Annelie Olofsson, Kristoffer Brännström, Intissar Anan, Anna L. Gharibyan, M Walfridsson |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Stereochemistry Calorimetry Ligands entalpic transthyretin Dissociation (chemistry) Plasma X-Ray Diffraction Drug Discovery Humans Prealbumin biology Chemistry Ligand nutritional and metabolic diseases Isothermal titration calorimetry Amyloidosis Blood proteins Small molecule Transport protein Transthyretin Drug Design biology.protein Thermodynamics Molecular Medicine Selectivity enthropic Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 58:6507-6515 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b00544 |
| Popis: | The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design. |
| Databáze: | OpenAIRE |
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