Tesis doctoral de Marta Pinto Manresa
The aim of this thesis was the design of new inhibitors of the bcl-xl/bcl-2 and ttr proteins by means of computational tools from the computer-aided drug design field. These proteins are discussed separately in part i and ii of this thesis. part i: bcl-2 proteins are critical regulators of the programmed cell death or apoptosis. Overexpression of different bcl-2 antiapoptotic proteins has been described in many cancers and is connected to chemo- and radiotherapy resistance. Accordingly, inhibition of these proteins represents attractive targets for novel anticancer agents. It is accepted that apoptosis is initiated by the binding of the bh3 domains from apoptotic proteins to the pro-survival molecules. Therefore, molecules that mimic these bh3 domains have potential as anticancer therapeutics. For this purpose, we have derived pharmacophore models for the bcl-xl and bcl-2 proteins from a molecular dynamics study of different bh3 peptides bound to each of them. These models were used for screening molecular databases. Several compounds were identified as novel small-molecule binders. After in vitro testing, five of the fifteen compounds commercially acquired were found to bind to the bcl-xl protein, but only one of them (ubqf03a-1) induced apoptosis and exhibited cell-permeability. In view of the ability of this compound to induce apoptosis in cancer cells, we have modelled its binding to bcl-xl for further optimization. We have also proposed new inhibitors by application of de novo techniques. part ii: ttr is a homotetrameric protein present in plasma and in the nervous central system, where is a carrier of thyroxine and other thyroid hormones. It is one of the human proteins that forms amyloid fibrils associated with diseases such as familial amyloid cardiomyopathy (fac), senile systemic amiloidosis (ssa) and familial polyneuropathy (fap). Ttr amyloid fibril formation requires the dissociation of the tetramer into monomeric species. It has been proven that the tetrameric structure of ttr can be stabilised by the binding of small ligands. In order to characterise their binding to this protein, we have analysed the crystallographic complexes available from the pdb. Furthermore, thyroid hormones are the only human biochemicals presenting multiple iodine atoms in their molecules. In this work, we have provided initial evidences for the hypothesis that incorporation of iodine atoms to known ttr inhibitors could increase their inhibitory potency. We have also proposed new analogs of 5-iododiflunisal, lead of the present work, by means of the use of molecular descriptors and docking studies.
Datos académicos de la tesis doctoral «Diseño asistido por ordenador de inhibidores de las dianas terapeuticas bcl-xl/bcl-2 y ttr«
- Título de la tesis: Diseño asistido por ordenador de inhibidores de las dianas terapeuticas bcl-xl/bcl-2 y ttr
- Autor: Marta Pinto Manresa
- Universidad: Politécnica de catalunya
- Fecha de lectura de la tesis: 28/07/2008
Dirección y tribunal
- Director de la tesis
- Juan Jesús Perez Gonzalez
- Tribunal
- Presidente del tribunal: gregorio Valencia parera
- enrique Perez paya (vocal)
- Ana m. Damas (vocal)
- ibón Alkorta osoro (vocal)