Propuesta de un protocolo de cribado virtual para el diseño de nuevos inhibidores selectivos de fosfodiesterasa 5 en el tratamiento de enfermedades neurodegenerativas

Resum

Alzheimer's disease stands out for her high and increasing morbidity, mortality and social impact. In this pathology has been observed an interruption of the mechanism to save long-term memory. This interruption has demonstrated related to the overexpression of phosphodiesterase 5 (PDE5). The aim of this research is the development of a virtual screening protocol to identify new selective PDE5 inhibitors. The auxiliary target is to enlarge the scope of this protocol to assist the design of a selective PDE2, PDE3, PDE4 and PDE9 inhibitors. To approach this goal crystal structures of PDEs have been studied and it’s been detected in their active site 5 sub-regions and 6 principal residues to join molecules to the target. Molecular models for the target are been prepared with MOE and AutoDockTools software and the molecular models for ligands are been prepared with Hyperchem and AutoDockTools software. Docking protocol has been validated through their application over PDE substrates and products and cocrystalized reference PDE inhibitor ligands. After analysis of the binding mode of PDE3, PDE4 and PDE5 inhibitors, there are proposed pharmacophoric models of the inhibitors. These results don’t allow preparing a good discernment method by virtual screening. It’s been improved Docking protocol and it’s been applied to different sets of PDE inhibitors. It’s been calculated the affinity energy against whole active site and the affinity against their sub-regions and principal residues interactions. Analysing interaction energy results it’s been proposed an initial method of discernment selective PDE5 inhibitors. This method is been evaluated as selective, but poor specific. This method is been improved by the identification of a complete energy profile using residues, sub-regions and total binding affinity against all PDEs studied using inverse docking increasing their specificity. The same protocol is been applied to build the initial and improved methods to identify PDE2, PDE3, PDE4 and PDE9 inhibitors. These methods are been applied to in house PDE inhibitors and it’s been selected different molecules as hits for their future development as new selective PDE inhibitors.