Energetic and structural analysis of organic and inorganic systems- the molecular modeling potentiality

The notable progresses achieved in the medical biotechnology research allowed to identify the common genetic origin of many different pathologies. Genes that, for unknown reasons, mutate during the lifetime of the patient synthesize proteins and receptors that lose the control by grow factors. These aberrant proteins are consequently always active and give rise to a series of cascade signals that result in an uncontrolled proliferation of tumor cells. In this framework, the use of small inhibitor molecules to deactivate these proteins, and consequently to block the diseases, constitutes a revolutionary concept that is the base of the †œtarget therapy†�. However, during the treatment, patients develop almost unavoidably resistance toward these kind of drugs that is caused by mutations that interest the amino acidic chains of determined tyrosine kinases (i.e. KIT, PDGFR?, etc.). In this thesis we used molecular modelling techniques to gain an insight in the binding between proteins and inhibitors. In particular, we were able to obtain unique information about the interactions that stabilize the complexation, and consequently about the destabilizing effect induced by mutations in the protein and receptor structures. Our data show that different drugs penetrate differently inside the binding site of kinases during the inhibition. Consequently, the efficiency of each inhibitor molecule is strongly dependent on the situation (mutations) presented by each patient. It becomes thus necessary to create a benchmark of responses related to all the most common mutations treated with different drugs. In this direction, molecular simulation can really support clinical scientists in the comprehension of drug resistance phenomena †" a virtual microscope, able to provide unique details to cancer research.