QSAR analysis of the toxicity of nitroaromatics in Tetrahymena pyriformis: structural factors and possible modes of action.

The Hierarchical Technology for Quantitative Structure-Activity Relationships (HiT QSAR) was applied to 95 diverse nitroaromatic compounds (including some widely known explosives) tested for their toxicity (50% inhibition growth concentration, IGC50) against the ciliate Tetrahymena pyriformis. The dataset was divided into subsets according to putative mechanisms of toxicity. The Classification and Regression Trees (CART) approach implemented within HiT QSAR has been used for prediction of mechanism of toxicity for new compounds. The resulting models were shown to have ~80% accuracy for external datasets indicating that the mechanistic dataset division was sensible. The Partial Least Squares (PLS) statistical approach was then used to develop 2D QSAR models. Validated PLS models were explored to: (1) elucidate the effects of different substituents in nitroaromatic compounds on toxicity; (2) differentiate compounds by probable mechanisms of toxicity based on their structural descriptors; and (3) analyse the role of various physical-chemical factors responsible for compounds' toxicity. Models were interpreted in terms of molecular fragments promoting or interfering with toxicity. It was also shown that mutual influence of substituents in benzene ring plays the determining role in toxicity variation. Although chemical mechanism based models were statistically significant and externally predictive (r²(ext) = 0.64 for the external set of 63 nitroaromatics identified after all calculations have been completed), they were also shown to have limited coverage (57% for modelling and 76% for external set).

[Artificial ribonucleases: quantitative analysis of the structure-activity relationship and new insight into the strategy of design of highly efficient RNase mimetics].

The dependence of hydrolytic activity of artificial ribonucleases toward an HIV-I RNA fragment, a 21-mer oligonucleotide, and tRNA Asp on the structure of the RNase mimetic was analyzed. The quantitative structure-activity relationship (QSAR task) was determined by the method of simplex representation of the molecular structure where the amounts of four-atom fragments (simplexes) of fixed structure, symmetry, and chirality served as descriptors. Not only the types of atoms participating in simplexes but also their physicochemical properties (e.g., partial charges, lipophilicities, etc.) were taken into account. This allowed the estimation of the relative role of various factors affecting the interaction of molecules under study with the corresponding biological target. The 2D QSAR models obtained by the method of projection to latent structures have quite satisfactory statistical indices (R2 = 0.82-0.96; Q2 = 0.73-0.89), which help predict the activities of new compounds. The electrostatic properties of ribonuclease atoms were shown to contribute significantly to the manifestation of the hydrolytic activity of ribonucleases in the case of the 21-mer oligonucleotide and tRNA. In addition, the structural fragments that most greatly contribute to the alteration of the hydrolytic activity of RNases were identified. The models obtained were used for the virtual screening and molecular design of new highly efficient RNase mimetics.

The effect of nitroaromatics' composition on their toxicity in vivo: novel, efficient non-additive 1D QSAR analysis.

Novel 1D QSAR approach that allows analysis of non-additive effects of molecular fragments on toxicity has been proposed. Twenty-eight nitroaromatic compounds including some well-known explosives have been chosen for this study. The 50% lethal dose concentration for rats (LD50) was used as the estimation of toxicity in vivo to develop 1D QSAR models on the framework of Simplex representation of molecular structure. The results of 1D QSAR analysis show that even the information about the composition of molecules provides the main trends of toxicity changes. The necessity of consideration of substituents' mutual impacts for the development of adequate QSAR models of nitroaromatics' toxicity was demonstrated. Statistic characteristics for all the developed partial least squares QSAR models, except the additive ones are quite satisfactory (R2=0.81-0.92; Q2=0.64-0.83; R2 test=0.84-0.87). A successful performance of such models is due to their non-additivity i.e. possibility of taking into account the mutual influence of substituents in benzene ring which plays the governing role for toxicity change and could be mediated through the different C-H fragments of the ring. The correspondence between observed and predicted by these models toxicity values is good. This allowing combine advantages of such approaches and develop adequate consensus model that can be used as a toxicity virtual screening tool.

Quantitative structure-affinity relationship of 5-HT1A receptor ligands by the classification tree method.

The influence of molecular structure of 346 ligands on their affinity for 5-HT1A receptors was investigated. It was shown that the effectiveness of the proposed novel approach for interpretation of decision tree models compared favourably with the PLS method. In the context of the proposed approach, molecular fragments and their values of the relative influence on the affinity for 5-HT1A receptors were defined.

Hierarchical QSAR technology based on the Simplex representation of molecular structure.

This article is about the hierarchical quantitative structure-activity relationship technology (HiT QSAR) based on the Simplex representation of molecular structure (SiRMS) and its application for different QSAR/QSP(property)R tasks. The essence of this technology is a sequential solution (with the use of the information obtained on the previous steps) to the QSAR problem by the series of enhanced models of molecular structure description [from one dimensional (1D) to four dimensional (4D)]. It is a system of permanently improved solutions. In the SiRMS approach, every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition, structure, chirality and symmetry). The level of simplex descriptors detailing increases consecutively from the 1D to 4D representation of the molecular structure. The advantages of the approach reported here are the absence of "molecular alignment" problems, consideration of different physical-chemical properties of atoms (e.g. charge, lipophilicity, etc.), the high adequacy and good interpretability of obtained models and clear ways for molecular design. The efficiency of the HiT QSAR approach is demonstrated by comparing it with the most popular modern QSAR approaches on two representative examination sets. The examples of successful application of the HiT QSAR for various QSAR/QSPR investigations on the different levels (1D-4D) of the molecular structure description are also highlighted. The reliability of developed QSAR models as predictive virtual screening tools and their ability to serve as the base of directed drug design was validated by subsequent synthetic and biological experiments, among others. The HiT QSAR is realized as a complex of computer programs known as HIT QSAR: software that also includes a powerful statistical block and a number of useful utilities.

Identification of individual structural fragments of N,N'-(bis-5-nitropyrimidyl)dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds.

OBJECTIVES: The objectives of this study were (i) to apply computer-based technologies to evaluate the structure of 48 N,N'-(bis-5-nitropyrimidyl)dispirotripiperazines which belong to a new class of highly active antiviral compounds binding to cell surface heparan sulphates, (ii) to understand the chemical- biological interactions governing their activities, and (iii) to design new compounds with strong antiviral activity. METHODS: The logarithm of 50% cytotoxic concentration (CC(50)) in GMK cells, of 50% inhibitory concentration (IC(50)) against herpes simplex virus type 1, and of selectivity index (SI = CC(50)/IC(50)) was used to develop quantitative structure-activity relationships (QSARs) based on simplex representation of molecular structure. The QSAR model was applied to design new compounds. Two of these compounds were synthesized, physico-chemically characterized and tested for cytotoxicity and antiviral activity. RESULTS: Statistic characteristics for partial least squares models allow the prediction of CC(50), IC(50) and SI values. The QSAR results demonstrate a high impact of individual structural fragments for antiviral activity. Molecular fragments that promote and interfere with antiviral activity were defined on the basis of the obtained models. Electrostatic factors (38%) and hydrophobicity (34%) were the most important determinants of antiherpetic activity. Using the established method, new potential dispirotripiperazine derivatives were computationally designed. Two of these computationally designed compounds were synthesized. The biological test results confirm the computationally predicted values of these compounds. CONCLUSIONS: The established QSAR model is suitable for the design of new antiherpetic compounds and prediction of their activity.

Structure--antiadenoviral activity of nitrogen containing macroheterocycles and their analogues.

The search for the inhibitors of adenoviruses has been performed among the substances of new class NCM (nitrogen containing macroheterocycles) and their analogues that have high potential of pharmacological properties. We have found a number of NCM and their derivatives that inhibit the reproduction of adenoviruses to various degrees. For the prediction of NCM structure with antiadenoviral activity we have performed the computer modeling using QSAR approach on the basis of simplex representation of molecular structure (SiRMS).

Investigation of anticancer activity of macrocyclic Schiff bases by means of 4D-QSAR based on simplex representation of molecular structure.

Influence of the molecular structure of macrocyclic pyridinophanes, their analogues and some other compounds on anticancer activity (Leukemia, central nervous system (CNS) cancer, prostate cancer, breast cancer, melanoma, non-small cell lung cancer, colon cancer, ovarian cancer, renal cancer) was investigated by means of a new 4D-QSAR approach based on the simplex representation of molecular structures (SiRMS). For all the investigated molecules, the 3D structural models were first created and the set of conformers (fourth dimension) was used. Each conformer was represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). Statistic characteristics of the QSAR partial least squares (PLS) models were satisfactory (correlation coefficient r=0.990-0.861; cross-validation coefficient CVR=0.914-0.633). The molecular fragments increasing and decreasing anticancer activity were defined. This information may be useful for the design and direct synthesis of novel anticancer agents.

[Hemosorption in intensive care treatment of severe forms of bronchial asthma in children]. / Gemosorbtsiia v programmakh intensivnoi terapii tiazhelykh form bronkhial'noi astmy u detei.

Addition of hemoperfusion to therapy of 40 children aged 2 to 16 years suffering from grave forms of asthma brought about therapeutic effects of different intensity. The efficacy of the procedure depended on preoperative treatment. The results permit a conclusion about the desirability of investigating the immune status and biochemical homeostasis for predicting the treatment effect and the remission.

[Intensive care of myelotoxic agranulocytosis using nonselective plasmapheresis]. / Intensivnaia terapiia mielotoksicheskogo agranulotsitoza s pomoshchíu neselektivnogo plazmafereza.

Plasmapheresis had a marked therapeutic effect in 14 cancer patients with grave myelotoxic complications of antitumor therapy: 13 of these patients survived, felt better, isosensitization to drugs and blood preparations was eliminated, the efficacy of common detoxifying and blood-substituting therapy improved. The therapeutic effect of the procedure was obvious even in the patient who died: the anuretic stage of acute renal failure changed for the polyuretic one. Plasmapheresis caused the most pronounced shifts in the system of homeostasis maintenance. The activation of the organism's autocleansing was attended by positive laboratory and clinical shifts.

[Experience in using plasmapheresis in comprehensive therapy of myelotoxic agranulocytosis in cancer patients]. / Opyt ispol'zovaniia plazmafereza v kompleksnoi terapii mielotoksicheskogo agranulotsitoza u onkologicheskikh bol'nykh.

Plasmapheresis was applied in 10 patients given chemotherapy and radiation treatment for myelotoxic agranulocytosis. After 1-3 sessions the patients improved, recovered hemopoiesis and normal protein metabolism. Of 10 patients 9 survived.

[Experimental study of therapeutic efficacy of plasmapheresis in acute radiation injury]. / Eksperimental'noe issledovanie terapevticheskoi éffektivnosti plazmafereza pri ostrom radiatsionnom porazhenii.

In experiments with dogs exposed to 2.9 Gy (LD80/45) it was found that plasmapheresis treatment 4-6 h after irradiation reduce the severity of the radiation sickness clinical manifestations and post-radiation toxemia thus increasing the rate of animal survival up to 60%. Sham plasmapheresis included all the manipulations of plasmapheretic treatment except plasma substitution and had no detoxication effect and did not affect the irradiated animals survival. This is evidence for leading role of detoxication in the mechanisms of the therapeutic action of plasmapheresis in acute irradiation.