Sandbox Reserved 1105: Difference between revisions

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The fibril formation inhibitors studied are ligands that resemble to the natural ligand T4 but more efficient in binding TTR, leading to a decrease of the amyloidogenic potential. The first potent amyloid inhibitors developed were non-steroidal anti-inflammatory drugs (NSAID), such as flufenamic acid ([[1bm7]]), diclofenac ([[1dvx]]), flurbiprofen ([[1dvt]]), indomethacin, diflunisal, meclofenamic acid, mefenamic acid, or fenoprofen.
The fibril formation inhibitors studied are ligands that resemble to the natural ligand T4 but more efficient in binding TTR, leading to a decrease of the amyloidogenic potential. The first potent amyloid inhibitors developed were non-steroidal anti-inflammatory drugs (NSAID), such as flufenamic acid ([[1bm7]]), diclofenac ([[1dvx]]), flurbiprofen ([[1dvt]]), indomethacin, diflunisal, meclofenamic acid, mefenamic acid, or fenoprofen.
However, regardless of a noticeable decrease of the TTR’s amyloidogenic potential <ref name="RD" />, prolonged NSAIDs administration could provoke renal failure, cardiac side effects, and gastrointestinal ulcers. <ref>Bally, M; Dendukuri, N; Rich, B; Nadeau, L; Helin-Salmivaara, A; Garbe, E; Brophy, JM (9 May 2017). "Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data". BMJ (Clinical Research Ed.). 357: j1909. PMC 5423546. PMID 28487435 doi: http://dx.doi.org/10.1136/bmj.j1909</ref> Gastric toxicity is linked to NSAID’s binding to a cyclooxygenase isoform, resulting in an inhibition of the activity of COX-1 and/or COX-2 associated to prostaglandin’s negative regulation. <ref name="RD" />
However, regardless of a noticeable decrease of the TTR’s amyloidogenic potential <ref name="RD" />, prolonged NSAIDs administration could provoke renal failure, cardiac side effects, and gastrointestinal ulcers. <ref>Bally, M; Dendukuri, N; Rich, B; Nadeau, L; Helin-Salmivaara, A; Garbe, E; Brophy, JM (9 May 2017). "Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data". BMJ (Clinical Research Ed.). 357: j1909. PMC 5423546. PMID 28487435 doi: http://dx.doi.org/10.1136/bmj.j1909</ref> Gastric toxicity is linked to NSAID’s binding to a cyclooxygenase isoform, resulting in an inhibition of the activity of COX-1 and/or COX-2 associated to prostaglandin’s negative regulation. <ref name="RD" />




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<Structure load='1dvu' size='340' frame='true' align='right' caption='Crystal Structure of human transthyretin in complex with dibenzofuran-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli [[resolution 2.05Å]] (PDB entry : [[1dvu]]) ' scene='Insert optional scene name here' />
<Structure load='1dvu' size='340' frame='true' align='right' caption='Crystal Structure of human transthyretin in complex with dibenzofuran-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli [[resolution 2.05Å]] (PDB entry : [[1dvu]]) ' scene='Insert optional scene name here' />




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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, 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"/>.  
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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 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.  
<ref name="Klabunde">PMID:10742177</ref>
<ref name="Klabunde">PMID:10742177</ref>


====Advantages====
====Advantages====
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