User:Léa Wick/Sandbox 1
From Proteopedia
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To exploit the TTR inner cavity, DDBR can be ameliorate [1]. An additional substituent like an aryl ring could be link at DDBR thought a heteroatom or directly via a covalent bond [2]. | To exploit the TTR inner cavity, DDBR can be ameliorate [1]. An additional substituent like an aryl ring could be link at DDBR thought a heteroatom or directly via a covalent bond [2]. | ||
For example, a N-phenyl phenoxazine-4,6-dicarboxylate, called Phenox (1dvy), allows to create additional bonds, which increase the kinetic stabilization of TTR. Besides, Van der Waals interactions are established with Thr106, Lys15, Leu17 from to adjacent TTR subunits. Moreover, the carboxylate groups link not only Lys15 but also Glu54 (carboxylate groups must to be protonated at physiological pH). In the side chain Leu17, Leu110 and Thr119 hydrophobic interactions take place with the trifluoromethyl group [1]. | For example, a N-phenyl phenoxazine-4,6-dicarboxylate, called Phenox (1dvy), allows to create additional bonds, which increase the kinetic stabilization of TTR. Besides, Van der Waals interactions are established with Thr106, Lys15, Leu17 from to adjacent TTR subunits. Moreover, the carboxylate groups link not only Lys15 but also Glu54 (carboxylate groups must to be protonated at physiological pH). In the side chain Leu17, Leu110 and Thr119 hydrophobic interactions take place with the trifluoromethyl group [1]. | ||
Unlike to a single DDBR, these substituted molecules make conformational change on side chains Thr119 and Ser117 with the formation of additional hydrogen bond. Furthermore, the water molecule in HBP3 pocket is displaced. [1] | Unlike to a single DDBR, these substituted molecules make conformational change on side chains Thr119 and Ser117 with the formation of additional hydrogen bond. Furthermore, the water molecule in HBP3 pocket is displaced. [1] | ||
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The substituted DDBR possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity [3]. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70% [3]. In vitro, the tetrameric structure of TTR is retained during 7 days with the N-phenyl phenoxazine-4,6-dicarboxylate, whereas without inhibitor TTR fibril formation takes place after 72h. [1] Additionally, these drugs don’t affect the cyclooxygenase activities [3]. Consequently, DDBR and its derivatives are potent drug for human transthyretin amyloid disease. | The substituted DDBR possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity [3]. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70% [3]. In vitro, the tetrameric structure of TTR is retained during 7 days with the N-phenyl phenoxazine-4,6-dicarboxylate, whereas without inhibitor TTR fibril formation takes place after 72h. [1] Additionally, these drugs don’t affect the cyclooxygenase activities [3]. Consequently, DDBR and its derivatives are potent drug for human transthyretin amyloid disease. | ||
Revision as of 12:11, 6 January 2020
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