2D QSAR аналiз проникаючої здатності органiчних сполук вiдносно поверхнi гематоенцефалiчного бар’єру

Abstract

Побудовано адекватні QSAR моделі «структура – показник проникнення речовин через гематоенцефалічний бар’єр (ГЕБ) LogPS» для органічних сполук різних класів. Проведено структурну та фізико-хімічну інтерпретацію моделей. Виявлено, що проникнення речовин через ГЕБ в значній мірі обумовлено гідрофобним чинником (30%). Визначено деякі фрагменти молекул, що сприяють або перешкоджають проникненню речовин через ГЕБ.

The aim of this work is to analyze the influence of the structure of organic compounds on their ability to penetrate the blood-brain barrier (BBB) using the values of LogPS (logarithm of the product of permeability and surface area of metabolism, which is a measure of the transfer of compounds from the blood to the brain and reflects the degree of penetration of the substance into the brain without relative binding to proteins). The study of the permeability of BBB is necessary both for the development of new drugs for which the CNS is a biointerference, and for the development of effective ways of treating diseases of the brain. At the initial stage of the study, the object of this work was the database of 89 organic compounds with a known value LogPS. Subsequently, the database was expanded to 177 compounds by additional data retrieval from various scientific sources. For all investigated compounds the structural parameters were calculated using the SiRMS method, which is based on the simplex representation of the molecular structure. QSAR models were developed using the “Partial Least Squares method” (PLS) and Random Forest (RF). The adequate «structure – LogPS» 2D-QSAR models were obtained for organic compounds of different classes. Physico-chemical and structural interpretation of the of the obtained QSAR models was carried out. Among various physical and chemical factors, the hydrophobic factors have the greatest influence on BBB permeability (30%). The study proved that polar groups and donor/acceptor of H-bond (–COOH, -NH2, -OH, -S(O)2-, -CO-, -NH-CO-) negatively affect the penetration ability of compounds through BBB. Contrary, aromatic fragments, halogens (–F, -Cl) and such fragments as different alkyls and -N(C2H5)2 have a positive effect on the penetration. The developed QSAR models were included in the expert system to predict the penetration of substances through the BBB.