Quantitative Structure-Activity Relationship in the Series of 5-Ethyluridine, N2-Guanine, and 6-Oxopurine Derivatives with Pronounced Anti-Herpetic Activity.

A quantitative analysis of the relationship between the structure and inhibitory activity against the herpes simplex virus thymidine kinase (HSV-TK) was performed for the series of 5-ethyluridine, N2-guanine, and 6-oxopurines derivatives with pronounced anti-herpetic activity (IC50 = 0.09 ÷ 160,000 µmol/L) using the GUSAR 2019 software. On the basis of the MNA and QNA descriptors and whole-molecule descriptors using the self-consistent regression, 12 statistically significant consensus models for predicting numerical pIC50 values were constructed. These models demonstrated high predictive accuracy for the training and test sets. Molecular fragments of HSV-1 and HSV-2 TK inhibitors that enhance or diminish the anti-herpetic activity are considered. Virtual screening of the ChEMBL database using the developed QSAR models revealed 42 new effective HSV-1 and HSV-2 TK inhibitors. These compounds are promising for further research. The obtained data open up new opportunities for developing novel effective inhibitors of TK.

QSPR Modeling and Experimental Determination of the Antioxidant Activity of Some Polycyclic Compounds in the Radical-Chain Oxidation Reaction of Organic Substrates.

The present work addresses the quantitative structure−antioxidant activity relationship in a series of 148 sulfur-containing alkylphenols, natural phenols, chromane, betulonic and betulinic acids, and 20-hydroxyecdysone using GUSAR2019 software. Statistically significant valid models were constructed to predict the parameter logk7, where k7 is the rate constant for the oxidation chain termination by the antioxidant molecule. These results can be used to search for new potentially effective antioxidants in virtual libraries and databases and adequately predict logk7 for test samples. A combination of MNA- and QNA-descriptors with three whole molecule descriptors (topological length, topological volume, and lipophilicity) was used to develop six statistically significant valid consensus QSPR models, which have a satisfactory accuracy in predicting logk7 for training and test set structures: R2TR > 0.6; Q2TR > 0.5; R2TS > 0.5. Our theoretical prediction of logk7 for antioxidants AO1 and AO2, based on consensus models agrees well with the experimental value of the measure in this paper. Thus, the descriptor calculation algorithms implemented in the GUSAR2019 software allowed us to model the kinetic parameters of the reactions underlying the liquid-phase oxidation of organic hydrocarbons.

QSAR Assessing the Efficiency of Antioxidants in the Termination of Radical-Chain Oxidation Processes of Organic Compounds.

Using the GUSAR 2013 program, the quantitative structure-antioxidant activity relationship has been studied for 74 phenols, aminophenols, aromatic amines and uracils having lgk7 = 0.01-6.65 (where k7 is the rate constant for the reaction of antioxidants with peroxyl radicals generated upon oxidation). Based on the atomic descriptors (Quantitative Neighborhood of Atoms (QNA) and Multilevel Neighborhoods of Atoms (MNA)) and molecular (topological length, topological volume and lipophilicity) descriptors, we have developed 9 statistically significant QSAR consensus models that demonstrate high accuracy in predicting the lgk7 values for the compounds of training sets and appropriately predict lgk7 for the test samples. Moderate predictive power of these models is demonstrated using metrics of two categories: (1) based on the determination coefficients R2 (R2TSi, R20, Q2(F1), Q2(F2), RmTSi2¯) and based on the concordance correlation coefficient (CCC)); or (2) based on the prediction lgk7 errors (root mean square error (RMSEP), mean absolute error (MAE) and standard deviation (S.D.)) The RBF-SCR method has been used for selecting the descriptors. Our theoretical prognosis of the lgk7 for 8-PPDA, a known antioxidant, based on the consensus models well agrees with the experimental value measure in the present work. Thus, the algorithms for calculating the descriptors implemented in the GUSAR 2013 program allow simulating kinetic parameters of the reactions underling the liquid-phase oxidation of hydrocarbons.

Molecular Docking and Preclinical Study of Five-Membered S,S-Palladaheterocycle as Hepatoprotective Agent.

Purpose: In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle, inhibition of cytochromes P450 has been modeled by molecular docking of four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system. To obtain a deeper insight into biochemical aspects providing a basis for the therapeutic effects of five-membered palladacycles (as mixture of stereoisomers), a number of preclinical trials has been conducted Methods: 2D and 3D structures of palladaheterocycle stereoisomers were obtained via converting into SDF files by means of software MarvinSketch. Binding of palladaheterocycle at the active sites of cytochromes P450 2E1 and P450 2C9 has been studied by molecular docking using LeadIT 2.3.2. Hepatoprotective activity of palladaheterocycle at 2.5, 25 and 250 mg/kg doses has been studied based on a model of acute intoxication by CCl4 using in vivo methods. Results: By molecular docking it was identify amino acid fragments responsible for binding with palladacyclic isomers. The tested compound is comparable, in terms of its activity to the hepatoprotective drug SAM according to the in vivo and in vitro experiments such as animal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretory function, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liver antitoxic function (the latter has been determined based on the results of a hexobarbital control experiment). Conclusion: Taking into account results obtained in vivo, in vitro and in silico, it can be concluded that the five-membered S,S-palladaheterocycle effectively protect the liver against acute damage caused by CCl4 , via activation of catalase and glucuronyltransferase, as well as via inhibition of the oxidative stress enzymes.

Quantitative structure-property relationship modeling of the C60 fullerene derivatives as electron acceptors of polymer solar cells: Elucidating the functional groups critical for device performance.

Using the GUSAR 2013 program, we have performed a quantitative analysis of the "structure-power conversion efficiency (PCE)" on the series of 100 methano[60]fullerenes previously tested as acceptor components of bulk-heterojunction polymer organic solar cells (PSCs) utilizing the same donor polymer, viz. poly(3-hexylthiophene). Based on the MNA and QNA descriptors and self-consistent regression implemented in the program, six statistically significant consensus models for predicting the PCE values of the methano[60]fullerene-based PSCs have been constructed. The structural fragments of the fullerene compounds leading to an increase in the device performances are determined. Based on these structural descriptors, we have designed the three methano[60]fullerenes included in the training sets and characterized by poor optoelectrical properties is performed. As a result, two new compounds with potentially moderate efficiency have been proposed. This result opens opportunities of using the GUSAR 2013 program for modeling of the "structure-PCE" relationship for diverse compounds (not only fullerene derivatives).

Quantitative structure-activity relationship of the thymidylate synthase inhibitors of Mus musculus in the series of quinazolin-4-one and quinazolin-4-imine derivatives.

A quantitative structure-activity relationship analysis of the 2-methylquinazolin-4-one and quinazolin-4-imine derivatives, well-known antifolate thymidylate synthase (TYMS) inhibitors, has been performed in the range IC50 = 0.4÷380000.0 nmoL/L using the GUSAR 2013 program. Based on the MNA and QNA descriptors using the self-consistent regression, 6 statistically significant consensus models for predicting the IC50 numerical values have been constructed. These models demonstrate high and moderate prognostic accuracies for the training and external validation test sets, respectively. The molecular fragments of TYMS inhibitors regulating their antitumor activity are identified. The obtained data open opportunities for developing novel promising inhibitors of TYMS.

Structural and Electronic Factors Influencing the Selective Inhibition of COX-2.

Structural and electronic factors influencing the inhibition of cyclooxygenase-1 and -2 (COX-1/COX-2) were studied by means of Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking and Density Functional Theory (DFT). A series of structurally diverse compounds containing 209 molecules were classified in accordance with their inhibiting properties, as selectively inhibiting and non-selectively inhibiting COX-2 receptor agents (110 and 99 molecules, correspondingly). The results obtained from the ETM-NN calculations gave us possibility of selecting those pharmacophoric molecular fragments, which allow for the search of new selective inhibitors of COX-2 with high probability of realization. The final selection of pharmacophores and anti-pharmacophores found was taken as a basis for a system designed for the COX-2 inhibitory activity prediction. Analysis of the electron density distribution showed that more effective binding with COX-2 receptor was observed for selective inhibitors. To make an assessment of these interactions, calculations of stabilization energies were carried out for the ligand-receptor complexes. From the results of the docking and from the analysis of electronic structures of active sites of enzymes, some peculiarities of ligand-receptor binding and its influence on the selectivity of the COX-2 relative to COX-1 inhibition were elucidated. 95% of compounds were recognized correctly, as the most active ones, by the system of prediction designed. Thus, the system being the result of the study is capable of predicting the selective inhibitory activity of COX-2 successfully. As a consequence, it can be used both for computer screening and synthesis of potent inhibitors of COX-2 with molecular skeletons that may vary considerably.