Etude théorique des réactions enzymatiques

Abstract

Xanthine oxidase is an ubiquitous cytoplasmic protein that catalyzes the last two steps of purine catabolism. It is one of the main sources of reactive oxygen species. The latest studies have shown its involvement in several pathologies such as diabetes, cardiovascular problems, ischemia -reperfusion, hyperuricemia and gout. Inhibition of this enzyme is necessary in the treatment or the prevention of several diseases. The interest of this work is based on the development of new inhibitors of xanthine oxidase which can serve as precursors in the development of a new drug capable of interacting with the target in a selective manner and with less adverse effects. In the first part, in silico modeling has allowed us to determine the type of interaction that is involved in the binding of six new ligands (CHAL1 - CHAL6) in the active site of XO. The results showed that complex CHAL / XO are more stable than which is formed by allopurinol (known as competitive inhibitor of XO, used as a drug against gout. So, quinoleic chalcones have a better affinity for the XO than allopurinol. To survive inside the human body and exercise their biological activity, bioavailability of these molecules was evaluated while calculating their pharmacokinetic properties from the Lipinski rules. In the second part, in vitro tests with the presence of CHAL1 CHAL2 allowed us to confirm the results found previously. At very low concentration, these two molecules could inhibit more than 70 % of the activity of xanthine oxidase.