[Computer modeling of blood brain barrier permeability of physiologically active compounds].

At present work discusses the current level of computer modeling the relationship structure of organic compounds and drugs and their ability to penetrate the BBB. All descriptors that influence to this permeability within classification and regression QSAR models are generalized and analyzed. The crucial role of H-bond in processes both passive, and active transport across BBB is observed. It is concluded that further research should be focused on interpretation the spatial structure of a full-size P-glycoprotein molecule with high resolution and the creation of QSAR models describing the quantitative relationship between structure and active transport of substances across BBB.

[Computer classification models on the relationship between chemical structures of compounds and drugs with their blood brain barrier penetration].

Ability of drugs to cross blood-brain barrier (BBB) (BBB+ for BBB-penetrating and BBB- for non-penetrating compounds) is one of the most important properties of chemicals acting on the central nervous system (CNS). This work presents the results of modelling of the relationship between chemicals structure and BBB-crossing ability. The data set included 1513 compounds BBB+/- (1276 BBB+ and 237 BBB-). Computer modelling of structure-activity relationship was realized by two directions: using the "read-across" method and linear discriminant analysis (LDA) based on physico-chemical descriptors. It was found that a sum of donor-acceptor factors is the principal parameter, which define BBB penetration.

[Acute intravenous toxicity to mice calculations on the basis local regression models in superoverlapping clusters (LRMSC)].

Modeling of quantitative structure--activity relationships between physicochemical descriptors of organic chemicals and their acute intravenous toxicity in mice have been presented. This approach includes three steps: structure-similarity chemicals selection for every chemical-of-interest (clusterization); construction of quantitative structure--toxicity models for every cluster (without including of chemical-of-interest); application of obtained QSAR equations for chemical-of-interest toxicity estimation. This approach has been applied for acute intravenous toxicity calculations of 10241 organic chemicals. For 7759 chemicals which has enough quantity of structural neighbours with the Tanimoto index (Tc) on the level 0.30 and over, a standard deviation of calculation vs. experimental log(1/LD50) values is equal to 0.51 at the estimation of experimental determination on the level 0.50. The results of calculations isn't so good for remain chemicals (approximately 24%). It is connect with absence of sufficient number of structure similarity neighbours. It's assumed this QSAR approach can be useful for activity and toxicity prediction of chemicals large sets.

[Linear and nonlinear QSAR models of acute intravenous toxicity to mice for organic chemicals].

QSAR analysis of acute intravenous toxicity to mice for 68 monofunctional chemicals is presented. There compounds represents seven classes of organic chemicals: hydrocarbons (6 chemicals), alcohols (13), amides (22), amines (12), ethers (5), ketones (7), nitriles (3). Preliminary consideration of data for these chemicals showed that it is necessary to consider not only linear toxicity--descriptors relationships, but also nonlinear models. The linear and nonlinear QSAR models were considered for each from indicated classes of organic chemicals. Analogical models were constructed for whole subset of monofunctional chemicals. The statistical parameters and robustness of nonlinear models are essential better then statistics of linear models. Replacing a lipophilicity descriptor with molecular polarizability and H-bond ability in nonlinear models permits also to improve statistical characteristics. Clearly, if relationships between the intravenous toxicity of compounds bearing only a single functional group and lipophilicity are nonlinear, then similar relationships must be considered with compounds containing more than one functional group. To check up this idea whole set of small clusters containing structure relative compounds with few functional groups was examined from position of linear and nonlinear relationships between toxicity and lipophilicity. It was estimated in most causes advantages of nonlinear models.

[Molecular modeling of acetylcholinesterase interaction with irreversible and reversible organophosphorous inhibitors].

Three-dimensional Quantitative Structure-Activity Relationship models were designed for irreversible and reversible acetylcholinesterase inhibitors by molecular modeling methods. In case of irreversible inhibitors CoMFA (the comparative analysis of molecular fields) or CoMSIA (the comparative analysis of indexes of molecular similarity) descriptors together with HYBOT 3D fields provide more statistically valid 3D-QSAR models. This indicates importance of donor-acceptor interactions for irreversible acetylcholinesterase inhibition. In case of reversible organophosphorous inhibitors good quality model for structure-activity relationships was developed using CoMFA fields. The obtained models have good predictive power and can be used for estimation of new organophosphorous compounds inhibitor activity that in turn correlates with toxicity of these compounds.

[Quantitative dependence of structure-antiseizure activity in a series of macrocyclic compounds]. / Kolichestvennaia zavisimost' struktura-protivosudorozhnaia aktivnost' v riadu makrotsiklicheskikh soedinenii.

In the present study we have further examined the influence of some structure parameters of macrocyclic polyethers upon their anticonvulsant activity in order to determine basic pharmacophore fragments. The anticonvulsant activity was studied experimentally for 25 new macrocyclic compounds, and their structure, physico-chemical properties, electron donor factors and atom charges were calculated using programs HyperChem-ChemPlus and HYBOT. The data about atomic properties were presented as a set functions of inter-atomic distances (Program MOLTRA). The cluster analysis revealed that studied compounds represent two independent groups which differ from chemical and pharmacological viewpoints. For first group, we have found that anticonvulsant activity of macrocycles is determined by their polarizability and spatial orientation of electron donor atoms. For another cluster the correlation was found between activity and spatial orientation of two hydrophobic fragments and electron donor atoms as well.

[Formation of models of the interaction between organophosphate compound structure and their ability to inhibit cholinesterase]. / Formirovanie modelei vzaimosviazi mezhdu strukturoi fosfororganicheskikh soedinenii i ikh sposobnost'iu k ingibirovaniiu kholinésteraz.

On the basis of a discrete-regression model earlier proposed by the authors, computer modelling of relationships between structure of organophosphorous compounds and their anticholinesterase activity was carried out. Values of kinetic constants of reversible and irreversible inhibition of human erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase by more than 240 phosphoryl and thiophosphoryl compounds (from own and literature data) were used as initial basis. For description of these compounds' structure informational-topological, physico-chemical and donor-acceptor descriptors were used. By means of procedures of discriminant, regression and cluster analysis, the compounds studied were divided into groups according to the structure, and quantitative structure--activity correlations were found in most of the clusters. This study revealed some functional peculiarities of these compounds and allowed for rationalisation of search of effective compounds with anticholinesterase activity.

[Synthetic Ca++-dependent proton carrier]. / Sinteticheskii Ca++-zavisimyi perenoschik protonov.

Influence of 1,5-(3,3'-dimethylphosphate)diphenoxy-3-oxapentane (DDOP) on conductivity (G) of bilayers of common fabbit brain lipids is studied. It has been found that DDOP increases the bilayer conductivity in the presence of Ca++ and Mg++ (G-maximum at pH = 7.0) they do not act in the presence of K+, Na+. pK'DDOP, pK"DDOP values are equal to 1.2, and 7.7 respectively as determined by titration. Formation of "pseudomacrocyclic" DDOP structure is suggested. The role of Ca++, Mg++ ions seems to consist in lipophilisation of ionized forms of DDOP.