Sandbox Reserved 1105: Difference between revisions

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====Improvements====
<Structure load='1dvy' size='340' frame='true' align='left' caption='Crystal Structure of human transthyretin in complex with N-(M-trifluoromethylphenyl) phenoxazine-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli [[resolution 1.09Å]] (PDB entry : [[1dvy]]) ' scene='Insert optional scene name here' />




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====Improvements====


To exploit the TTR inner cavity, DDBR 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 DDBR 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>.
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 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.  
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.  
<ref name="Klabunde">PMID:10742177</ref>
<ref name="Klabunde">PMID:10742177</ref>


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