Several drug discovery approaches has been performed to find new compounds able to interact with high affinity with the hormone binding site of the homotetrameric protein transthyretin (TTR), and stabilize this tetramer, becoming drug candidates to treat several rare amyloid diseases associated with TTR.
With this aim, several computational workflows and chemico-biological databases have been developed, and in collaboration with two experimental research laboratories of our TTR Consortium (one contributing with the chemical synthesis or acquisition of the designed compounds, and the other contributing with the biological activity assay results for the synthesized or acquired compounds).
The specific objectives of this thesis are:
a) The generation of a chemico-biological database containing the historical and newly generated results of the TTR Consortium, containing the chemical structures and biological activities of the TTR ligands.
b) Explore the possibility of using repurposing techniques applied to the discovery of new TTR inhibitors among the existing drugs, with particular focus on anti-inflammatory drugs, which are known to be good TTR ligands.
c) Design of new flavonoid compounds as TTR ligands by means of structure-based drug design.
d) Incorporate the Ligand Efficiency Indices analysis (both retrospective and prospective) as a new tool for designing new compounds with increased efficiency as TTR ligands.
e) The computational development of a combined predictive/experimental workflow for the analysis of the metabolic stability of TTR ligands, as a tool for improving the prioritized compounds in our in-house database to obtain new compounds with better metabolic and pharmacokinetic properties.
Among this thesis those workflows have been developed in order to obtain possible new amyloidogenic inhibitors:
a) A computational workflow to obtain TTR ligand fingerprints has been developed, and the application of this workflow to the repurposing of marketed antiinflammatory drugs has delivered 3 compounds as new TTR stabilizers.
b) A computational workflow to obtain a TTR-protein structure based pharmacophore has been developed, and the application of this workflow to a database of flavonoid compounds has delivered one compound as a new TTR stabilizer.
| Identifer | oai:union.ndltd.org:TDX_UB/oai:www.tdx.cat:10803/108283 |
| Date | 27 February 2013 |
| Creators | Blasi Pérez, Daniel |
| Contributors | Quintana Ruiz, Jordi Ramon, Boada Centeno, Núria, Albericio Palomera, Fernando, Universitat de Barcelona. Departament de Química Orgànica |
| Publisher | Universitat de Barcelona |
| Source Sets | Universitat de Barcelona |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | 154 p., application/pdf |
| Source | TDX (Tesis Doctorals en Xarxa) |
| Rights | info:eu-repo/semantics/openAccess, ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. |
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