Bortolato, Andrea (2008) Rational Design of New Protein Kinases Inhibitors of Pharmaceutical Interest. [Tesi di dottorato]
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Cells respond to externals cues thanks to several different signals cascade activated by transmembrane receptors as G coupled protein receptors and tyrosin kinase receptors. Signals are not simply transducted, but also amplified and propagated using a precise tuned elaborating system resulting in a well defined cell behaviour. In this contest, protein kinases are key enzymes for cell life, thanks to their signal transduction pathways control. A perturbation of their activity can in
fuence in an important way this essential equilibrium, resulting in several pathologies as cancer, diabetes and in
ammation. These enzymes act controlling substrates activity phosphoryling some specific residues of Serine, Threonine and Tyrosin, using an ATP molecule as phosphate donor. In this study have been studied principally two protein kinases, CK2 and Abl, implicated with the development and progression of several tumors. The first, know
also as Casein Kinase 2, is a pleiotropic, constitutively active protein demonstrated to be implicated in many physiological process and over-expressed in several cancer cell lines. On the other hand the protein tyrosin kinase Abelson (Abl), together with PDGFR and Kit enzymes, is the molecular cause of chronic
myelogenous Leukaemia and gastrointestinal stromal tumor.
Protein kinases are an interesting family of molecular targets for a new generation of antitumors drugs aiming the molecular mechanisms exploited by cancer to survive and develop. This study represents an attempt to reach this result by means of a rational approach to design new small organic molecules with a
potential antitumoral activity based on their inhibition of these protein kinases.
Methodologies used rely on the most advanced drug design computational techniques based on the threedimensional structure of the therapeutic target and they have been used only after a intense internal validation phase based on the
experimental data available in literature and on important collaborations with several research groups at national and international level.
Using these computational methodologies a complete study of CK2 ATP-binding pocket has been carried out, investiging its electrostatic features and creating several pharmacophoric hypothesis based on crystallographic structural data. These approaches helped us to evaluate from a qualitative point of
view the interactions crucials for the inhibitor-protein binding and to highlight the importance for the binding mode in the enzymatic pocket of some waters molecules. These informations have been the starting point for a quantitative Linear Interaction Energy (LIE) study of benzoimidazolic and coumarins derivatives. They have point out the key contribution of the hydrophobic effect to achieve a powerful inhibitor effect of CK2 and of van der Waals interactions with several apolar side chains characterizing the binding site of this kinase. On other hand the MM-PBSA approach has been used to analyze the different inhibition power, with important pharmacological implications on the selectivity, of the drug known as Gleevec (STI-571) and its similar analogue CGP-582 versus the protein kinase Abl. This method has been combined with success with the Colony Energy approach to improve the results robustness, diminishing the dependence of the free energy
of binding estimation from small conformational changes.
The key features knowledge for the inhibition is the first step for the drug discovery process based on biostructural information and the integrate computational protocol used in this study had allowed the comprehension of the chemical-physical peculiarities of therapeutical targets as well as ligands, allowing
the development of new inhibitors with potential antitumoral activity.
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