Kosinska H. Structural factors of molecules that determine their ability to penetrate the blood-brain barrier (BВВ)

Functioning of the blood-brain barrier. QSAR models for different parameters characterizing the permeability of substances through ВВB, structural and physicochemical factors of this process. Computer programs: MarvinSketch of the ChemAxon complex (ChemAxon Ltd, http://www.chemaxon.com), HyperChem (trial version, Hypercube Inc, http://www.hyper.com). “Data curation” methods were used for data processing. Standardization of the structures of investigate compounds: Standardizer programs (ChemAxon), search for errors, duplicates, structural analysis, calculation of 2D structural (simplex) descriptors - used HiTQSAR software. QSAR models of "structure - permeability through BBB" are build by methods of partial least squares (PLS - Partial Least Squares) and random forest (Random Forest).A database has been formed, a number of simplex (fragment) descriptors have been calculated, the vertices of which are differentiated according to different atomic properties. A number of adequate QSAR models for estimating the parameters of penetration of substances through BBB - LogBB, LogPS, LogP0PAMPA-BBB , belonging to the class BBB + / BBB-, substrate P-glycoprotein / non-substrate. Robustness and prognostic ability are estimated, areas of applicability domain of models are analyzed. Physico-chemical and structural interpretation of the constructed QSAR models is carried out. A comparative analysis of the influence of structural and physicochemical factors for all parameters of penetration through the BBB, the balance of polar and nonpolar factors. An expert system has been created to predict various penetration parameters through the BBB of organic compounds. Scope - bioorganic chemistry.