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• W1500720540 abstract "Nuclear Magnetic Resonance has experienced an increasing interest in the drug discovery field that has led to its wide use on nearly every stage of drug development. For this reason, during the present thesis we propose to use some of the tools offered by NMR to target various systems related with cancer.Initially we intended to get acquainted with the NMR most outstanding methodologies for the detection and characterization of binding events; and for this goal various proteins involved in cellular apoptosis (XIAP and Bcl-XL) were used to set up both ligand and receptor based NMR experiments. First we developed two novel labeling methodologies for the selective NMR observation of Trp, which coupled to the use of receptor-based experiments provided insight in the characterization of XIAP-ligand complexes, as well as significant advantages for HTS. Later, ligand based experiments such as STD, WaterLOGSY and iLOE were applied to the screening of weak binders for Bcl-XL, and the resulting information applied to the reconstruction of dual binders in a fragment-based drug discovery approach.In a second stage the same NMR tools were applied to the development of protein-protein interaction inhibitors, in particular for the pro-angiogenic protein VEGF; and to this end two different strategies were proposed. First, a small diverse library of D-oligopeptides was screened for weak ligands using the former fragment-based strategy. A second approach consisted on the identification of active compounds in complex plant extract mixtures using a combination of methionine selective labeling schemes and receptor-based experiments. In the latter case various flavonoids were identified as VEGF binders and the information harvested from NMR experiments allowed us to propose a binding mode for this type of molecules.Lastly, in a much more classic context, we decided to attempt the characterization of a medium sized oligopeptide by NMR. In particular we focused on Kahalalide F a marine origin depsipeptide with very promising anticancer activity; and although a SAR profile would be very useful from a medicinal chemistry perspective such molecules still pose a challenge to their structural characterization particularly stemming from its intrinsic flexibility. Several media were explored including H2O, DMSO, and membrane mimics (SDS micelles); in the latter the peptide seems to adopt a preferred structure allowing us to propose a model for the monomeric insertion of Kahalalide F within membrane-like environments. Such a model supports that part of the peptides cytotoxic activity occurs at a membrane level and that this activity is linked to the formation of a turn within its N-terminus section. RESUMEN:La resonancia magnetica nuclear se utiliza en la actualidad en practicamente todas las etapas del proceso de descubrimiento y caracterizacion de farmacos. Durante la presente tesis nos propusimos explorar estas facetas de la RMN tomando como modelo diferentes sistemas relacionados con cancer.En primer lugar utilizamos proteinas involucradas en apoptosis (XIAP y Bcl-XL) para implementar varias metodologias de RMN para la caracterizacion de fenomenos de interaccion intermolecular. Se pusieron a punto esquemas de marcaje selectivo de triptofano y se evaluo su aplicabilidad en procesos de cribado de compuestos. Otros experimentos de cribado masivo (STD, WaterLOGSY) se emplearon para identificar nuevos ligandos de Bcl-XL; posteriormente, estrategias de reconstruccion de fragmentos nos permitieron disenar ligandos duales.Las mismas herramientas se utilizaron para el diseno y desarrollo de moleculas antiangiogenicas, inhibidoras de la interaccion entre VEGF y sus receptores. Para este fin, se plantearon dos estrategias diferentes en la identificacion de inhibidores: en primer lugar se pretendia disenar un ligando peptidico de afinidad elevada partiendo de dipeptidos de menor afinidad y utilizando estrategias de reconstruccion de fragmentos. Una segunda estrategia consistia en la identificacion de compuestos activos presentes en extractos de plantas utilizando esquemas de marcaje selectivo para VEGF, en concreto marcaje selectivo de metioninas. En este ultimo caso se consiguieron identificar varios compuestos flavonoides capaces de interaccionar con VEGF y su modo de union se caracterizo utilizando informacion derivada de experimentos de RMN.Por ultimo se llevo a cabo la caracterizacion estructural de Kahalalido F mediante RMN. Este depsipeptido de origen marino se encuentra en la actualidad en fases clinicas de desarrollo contra varios tipos de cancer, y su caracterizacion estructural presenta enorme interes en la comprension de su modo de accion. Se exploraron las preferencias conformacionales del peptido en varios medios incluyendo: H2O, DMSO, y medios mimeticos de membrana (micelas SDS). El peptido adopta una estructura preferente en presencia de micelas de SDS, lo que nos permiten proponer un modelo estructural para la insercion monomerica de Kahalalido F en entornos de membrana lipidica; esto sugiere que parte de su actividad citotoxica ocurre a nivel de membrana para lo cual la formacion de un giro ? en la seccion N-terminal del peptido tambien parece relevante. " @default.
• W1500720540 created "2016-06-24" @default.
• W1500720540 creator A5045021711 @default.
• W1500720540 creator A5059011831 @default.
• W1500720540 date "2006-10-05" @default.
• W1500720540 modified "2023-09-26" @default.
• W1500720540 title "NMR in drug discovery. From screening to structure-based design of antitumoral agents" @default.
• W1500720540 cites W115748941 @default.
• W1500720540 cites W1500228509 @default.
• W1500720540 cites W1518078436 @default.
• W1500720540 cites W1520252425 @default.
• W1500720540 cites W1531494225 @default.
• W1500720540 cites W1532861168 @default.
• W1500720540 cites W1539571840 @default.
• W1500720540 cites W154686786 @default.
• W1500720540 cites W1552774315 @default.
• W1500720540 cites W1557686543 @default.
• W1500720540 cites W1601592303 @default.
• W1500720540 cites W1607777232 @default.
• W1500720540 cites W1775942876 @default.
• W1500720540 cites W1872921923 @default.
• W1500720540 cites W1900730650 @default.
• W1500720540 cites W1964311344 @default.
• W1500720540 cites W1965217295 @default.
• W1500720540 cites W1967651152 @default.
• W1500720540 cites W1967968677 @default.
• W1500720540 cites W1968619018 @default.
• W1500720540 cites W1969061926 @default.
• W1500720540 cites W1969156185 @default.
• W1500720540 cites W1969262500 @default.
• W1500720540 cites W1971914602 @default.
• W1500720540 cites W1972091733 @default.
• W1500720540 cites W1972171404 @default.
• W1500720540 cites W1972237128 @default.
• W1500720540 cites W1973621188 @default.
• W1500720540 cites W1975071709 @default.
• W1500720540 cites W1976230851 @default.
• W1500720540 cites W1976935037 @default.
• W1500720540 cites W1977179663 @default.
• W1500720540 cites W1979598348 @default.
• W1500720540 cites W1980102481 @default.
• W1500720540 cites W1983041459 @default.
• W1500720540 cites W1984689230 @default.
• W1500720540 cites W1985913381 @default.
• W1500720540 cites W1986765845 @default.
• W1500720540 cites W1986962635 @default.
• W1500720540 cites W1988326008 @default.
• W1500720540 cites W1988620274 @default.
• W1500720540 cites W1993257312 @default.
• W1500720540 cites W1995601809 @default.
• W1500720540 cites W1996211903 @default.
• W1500720540 cites W1996913951 @default.
• W1500720540 cites W1997282155 @default.
• W1500720540 cites W1998274788 @default.
• W1500720540 cites W1999187807 @default.
• W1500720540 cites W1999350919 @default.
• W1500720540 cites W1999474252 @default.
• W1500720540 cites W2000292756 @default.
• W1500720540 cites W2000624254 @default.
• W1500720540 cites W2000880755 @default.
• W1500720540 cites W2001648837 @default.
• W1500720540 cites W2002586148 @default.
• W1500720540 cites W2004967944 @default.
• W1500720540 cites W2005476159 @default.
• W1500720540 cites W2005923596 @default.
• W1500720540 cites W2006842696 @default.
• W1500720540 cites W2007042842 @default.
• W1500720540 cites W2009488215 @default.
• W1500720540 cites W2011395093 @default.
• W1500720540 cites W2012815507 @default.
• W1500720540 cites W2013600324 @default.
• W1500720540 cites W2014196693 @default.
• W1500720540 cites W2014860988 @default.
• W1500720540 cites W2015879631 @default.
• W1500720540 cites W2017312554 @default.
• W1500720540 cites W2018221677 @default.
• W1500720540 cites W2019074781 @default.
• W1500720540 cites W2024105848 @default.
• W1500720540 cites W2025297513 @default.
• W1500720540 cites W2027318109 @default.
• W1500720540 cites W2028212425 @default.
• W1500720540 cites W2029031988 @default.
• W1500720540 cites W2029412165 @default.
• W1500720540 cites W2029651134 @default.
• W1500720540 cites W2030608812 @default.
• W1500720540 cites W2030829227 @default.
• W1500720540 cites W2031703162 @default.
• W1500720540 cites W2032745254 @default.
• W1500720540 cites W2034444864 @default.
• W1500720540 cites W2034893085 @default.
• W1500720540 cites W2035833108 @default.
• W1500720540 cites W2037490361 @default.
• W1500720540 cites W2038821178 @default.
• W1500720540 cites W2039597975 @default.
• W1500720540 cites W2039811523 @default.
• W1500720540 cites W2040590040 @default.
• W1500720540 cites W2040987426 @default.
• W1500720540 cites W2041774091 @default.
• W1500720540 cites W2042584758 @default.
• W1500720540 cites W2043922597 @default.

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