Keywords
Abstract
The pathogenesis of the most common human diseases of the cardiovascular system, respiratory tract, malignant neoplasms is characterized by fairly well-defined free radical phase. Therefore, an important task of modern pharmacology is the search and creation of highly effective antioxidants. For preliminary antioxidant activity (AOA) assessment an information technology and computer programs for virtual screening are developing. So the development of approaches to the creation of computer programs for antioxidant activity prediction, namely NO scavengers, is a promising and actual direction of modern fundamental medicine. The purpose of research – to develop a highly selective program for AOA virtual screening on the basis of complex mathematical and theoretical approaches and the results of pharmacological studies of a number of xanthine derivatives. As the objects of the study were selected 122 derivatives of xanthinyl-7-acetate, xanthinyl-8-thioacetate acids and 3-R-hydroxymethylxanthines. For these compounds were performed quantum chemical calculations in particular the descriptors of energy molecular orbital, as well as AOA study in vitro by inhibition of NO radical under photo induced oxidation in sodium nitroprusside system. Subsequently the correlations between quantum-chemical parameters of the compounds and AOA (by NO radical inhibition) were calculated. It has been shown how to apply the electronic topological approach that allows searching for molecular fragments – activity signs. There were calculated quantum-chemical parameters of the investigated molecules using the CNDO/2 method: the indicators of energy limiting orbitals (LUMO, HOMO), indicators of absolute hardness (rigidity), absolute electrical negativity of the molecule. From these data such indicator as reactivity index was calculated. The dependence of compound’s АОА (by NO radical inhibition) on their quantum-chemical descriptors and their function were determined. For the creation of software for the screening of potential NO scavengers were selected quantum chemical descriptors. Based on the chemical nature and the reactivity of nitrogen active forms, particular attention should be paid to the energies of the highest occupied and lowest unoccupied molecular orbitals, and Fukui reactivity index. New computer program developed on the basis of an integrated approach (combination of theoretical concepts, mathematical methods, rules and their algorithms) is a highly effective tool for virtual NO scavengers screening in a series of newly synthesized structurally-similar azaheterocycles that proved by computing testing and confirmed by experimental studies. Thus, the use of a new computer program for АОА prediction allowed to reveal the newly synthesized compound – 8-benzylaminotheophyllinyl-7-acetic acid hydrazide (C-3) as NO scavenger.