Ryzhenko V. Optimization of purposeful search of NO scavengers in a number of xanthine derivatives

The dissertation is devoted to the actual task of modern pharmacology – the search for new effective antioxidants among xanthine derivatives for use in the treatment of myocardial and cerebral ischemia. The work is carried out for evaluation of the antioxidant activity of 122 xanthine derivatives in vitro with respect to NO inhibition. The dependence of antioxidant activity on quantum chemical parameters of xanthine derivatives was analyzed using machine learning algorithms using the following models: Linear Regression, Support Vector Machine Regression, Random Forest Regression, Gradient Boosting Regression, K-Nearest Neighbors Regression. As a result of our analysis, we tested several models for solving regression problems. The best models without the use of optimization were the models of "Reference vectors" and "K-nearest neighbors". According to the main indicators of anti-ischemic and antioxidant action in experimental myocardial infarction, acute working hypoxia and intracerebral hemorrhage, C-3 is significantly superior to reference drugs (Mildronate, Mexidol and Piracetam). Antiischemic action of C-3 in experimental myocardial infarction, working hypoxia and intracerebral hemorrhage is determined by its properties of the NO scavenger and is aimed at interrupting the ROS/SH-dependent mechanisms of energy metabolism disorders, deprivation of the endogenous cytoprotection system, reduced physical endurance and cognitive deficit. The created computer program is a highly efficient and selective tool for virtual screening of NO scavengers in a number of newly synthesized structural-eastern azaheterocycles, which has been proven by computational testing and confirmed by experimental studies and can be used to optimize targeted search for new antioxidants and newly synthesized compounds. The experimentally established mechanism of action of the xanthine derivative − C-3 can contribute to the creation of a new generation of effective drugs with antioxidant action, interrupting NO-dependent links of ischemic damage to the myocardium and brain.