Sandbox Reserved 1105: Difference between revisions

Line 156:

====Improvements====

To exploit the TTR inner cavity, DDBF can be ameliorate <ref name="Klabunde">PMID:10742177</ref>. An additional substituent like an aryl ring could be link at ~~DDBR~~ thought a heteroatom or directly via a covalent bond <ref name="Petrassi"/>.

To exploit the TTR inner cavity, DDBF can be ameliorate <ref name="Klabunde">PMID:10742177</ref>. An additional substituent like an aryl ring could be link at DDBF thought a heteroatom or directly via a covalent bond <ref name="Petrassi"/>.

For example, a N-phenyl phenoxazine-4,6-dicarboxylate, called Phenox (PDB entry : [[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 <ref name="Klabunde">PMID:10742177</ref>.

Unlike to a single DDBF, 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.

Line 163:

====Advantages====

The substituted ~~DDBR~~ possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity <ref name="Labaudinière"/>

The substituted DDBF possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity <ref name="Labaudinière"/>

<ref name="National Center for Biotechnology Information">CID:3022,https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid</ref>. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70%. 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.<ref name="Klabunde">PMID:10742177</ref> Additionally, these drugs don’t affect the cyclooxygenase activities <ref name="Labaudinière"/>. Consequently, ~~DDBR~~ and its derivatives are potent drug for human transthyretin amyloid disease.

<ref name="National Center for Biotechnology Information">CID:3022,https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid</ref>. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70%. 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.<ref name="Klabunde">PMID:10742177</ref> Additionally, these drugs don’t affect the cyclooxygenase activities <ref name="Labaudinière"/>. Consequently, DDBF and its derivatives are potent drug for human transthyretin amyloid disease.

== References ==

Sandbox Reserved 1105: Difference between revisions

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@@ Line 156: / Line 156: @@
 ====Improvements====
-To exploit the TTR inner cavity, DDBF can be ameliorate <ref name="Klabunde">PMID:10742177</ref>. An additional substituent like an aryl ring could be link at DDBR thought a heteroatom or directly via a covalent bond <ref name="Petrassi"/>.
+To exploit the TTR inner cavity, DDBF can be ameliorate <ref name="Klabunde">PMID:10742177</ref>. An additional substituent like an aryl ring could be link at DDBF thought a heteroatom or directly via a covalent bond <ref name="Petrassi"/>.
 For example, a N-phenyl phenoxazine-4,6-dicarboxylate, called Phenox (PDB entry : [[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 <ref name="Klabunde">PMID:10742177</ref>.
 Unlike to a single DDBF, 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.
@@ Line 163: / Line 163: @@
 ====Advantages====
-The substituted DDBR possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity <ref name="Labaudinière"/>
+The substituted DDBF possess numerous advantages. In vivo, at a molar ratio of 1, there is more of 50% of fibril inhibition activity <ref name="Labaudinière"/>
-<ref name="National Center for Biotechnology Information">CID:3022,https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid</ref>. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70%.  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.<ref name="Klabunde">PMID:10742177</ref> Additionally, these drugs don’t affect the cyclooxygenase activities <ref name="Labaudinière"/>. Consequently, DDBR and its derivatives are potent drug for human transthyretin amyloid disease.
+<ref name="National Center for Biotechnology Information">CID:3022,https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid</ref>. The occupancy of the TTR and the energetically favourable interactions reduce tetrameric dissociation by 70%.  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.<ref name="Klabunde">PMID:10742177</ref> Additionally, these drugs don’t affect the cyclooxygenase activities <ref name="Labaudinière"/>. Consequently, DDBF and its derivatives are potent drug for human transthyretin amyloid disease.
 == References ==
 <references/>