Goran M. Nikolić

Synthesis, physicochemical and spectroscopic characterization of copper(II)-polysaccharide pullulan complexes by UV–vis, ATR-FTIR, and EPR

Bioactive copper(II) complexes with polysaccharides, like pullulan and dextran, are important in both veterinary and human medicine for the treatment of hypochromic microcitary anemia and hypocupremia. In aqueous alkaline solutions, Cu(II) ion forms complexes with the exopolysaccharide pullulan and its reduced low-molecular derivative. The metal content and the solution composition depend on pH, temperature, and time of the reaction. The complexing process begins in a weak alkali solution (pH >7) and involves OH groups of pullulan monomer (glucopyranose) units. Complexes of Cu(II) ion with reduced low-molecular pullulan (RLMP, M(w) 6000 g mol(-1)) were synthesized in water solutions, at the boiling temperature and at different pH values ranging from 7.5 to 12. The Cu(II) complex formation with RLMP was analyzed by UV-vis spectrophotometry and other physicochemical methods. Spectroscopic characterizations (ATR-FTIR, FT-IRIS, and EPR) and spectra-structure correlation of Cu(II)-RLMP complexes were also carried out.

SMILES-based QSAR model for arylpiperazines as high-affinity 5-HT1A receptor ligands using CORAL

A predictive quantitative structure - activity relationships model of arylpiperazines as high-affinity 5-HT(1A) receptor ligands was developed using CORAL software (http://www.insilico.eu/CORAL). Simplified molecular input-line entry system (SMILES) was used as representation of the molecular structure of the arylpiperazines. The balance of correlations was used in the Monte Carlo optimization aimed to build up optimal descriptors for one-variable models. The robustness of this model has been tested in four random splits into the sub-training, calibration, and test set. The obtained results reveal good predictive potential of the applied approach: correlation coefficients (r²) for the test sets of the four random splits are 0.9459, 0.9249, 0.9473 and 0.9362.

SMILES‐Based QSAR Models for the Calcium Channel‐Antagonistic Effect of 1,4‐Dihydropyridines

The activity of 72 1,4‐dihydropyridines as calcium channel antagonists was examined. The simplified molecular input‐line entry system (SMILES) was used as representation of the molecular structure of the calcium channel antagonists. Quantitative structure–activity relationships (QSARs) were developed using CORAL software (http://www.insilico.eu/CORAL) for four random splits of the data into the training and test sets. Using the Monte Carlo method, the CORAL software generated the optimal descriptors for one‐variable models. The reproducibility of each model was tested performing three runs of the Monte Carlo optimization. The obtained results reveal good predictive potential of the applied approach: The correlation coefficients (r2) for the test sets of the four random splits are 0.9571, 0.9644, 0.9836, and 0.9444.

Antioxidant properties of selected 4-phenyl hydroxycoumarins: Integrated in vitro and computational studies.

A study on the structure-activity relationship of three hydroxy 4-phenyl coumarins, carried out by employing a series of different chemical cell-free tests is presented. Different assays involving one redox reaction with the oxidant (DPPH, ABTS, FRAP and CUPRAC) were employed. Further, the measurement of inhibition of oxidative degradation, such as lipid peroxidation, was used to define compound antioxidant activity. Our results confirm the good antioxidant activity of the 7,8-dihydroxy-4-phenyl coumarin and moderate antioxidant activity of 5,7-dihydroxy-4-phenyl coumarin. In this work, quantum chemical calculations based on density functional theory have been employed at B3LYP/6-311++G(d,p) level of theory to study the influence of number and position of hydroxyl groups in coumarin molecules on antioxidant activity. Calculated values for HOMO and LUMO energies, energy gap, stabilization energies and spin density distribution confirmed experimental results and were used for SAR definition. For determination of reaction mechanism in gas phase and selected solvents bond dissociation enthalpy, adiabatic ionization potential, proton dissociation enthalpy, proton affinity, electron transfer enthalpy and gas phase acidity have been calculated. Hydrogen Atom Transfer mechanism in vacuum and Single-Electron Transfer followed by the Proton Transfer mechanism in other studied systems are most probable free radical scavenging pathways. On the basis of these findings, these hydroxy 4-phenyl coumarins may be considered as potential therapeutic candidates for pathological conditions characterized by free radical overproduction.

Monte Carlo QSAR models for predicting organophosphate inhibition of acetycholinesterase

A series of 278 organophosphate compounds acting as acetylcholinesterase inhibitors has been studied. The Monte Carlo method was used as a tool for building up one-variable quantitative structure–activity relationship (QSAR) models for acetylcholinesterase inhibition activity based on the principle that the target endpoint is treated as a random event. As an activity, bimolecular rate constants were used. The QSAR models were based on optimal descriptors obtained from Simplified Molecular Input-Line Entry System (SMILES) used for the representation of molecular structure. Two modelling approaches were examined: (1) ‘classic’ training-test system where the QSAR model was built with one random split into a training, test and validation set; and (2) the correlation balance based QSAR models were built with two random splits into a sub-training, calibration, test and validation set. The DModX method was used for defining the applicability domain. The obtained results suggest that studied activity can be determined with the application of QSAR models calculated with the Monte Carlo method since the statistical quality of all build models was very good. Finally, structural indicators for the increase and the decrease of the bimolecular rate constant are defined. The possibility of using these results for the computer-aided design of new organophosphate compounds is presented.

Monte Carlo Method‐Based QSAR Modeling of Penicillins Binding to Human Serum Proteins

The binding of penicillins to human serum proteins was modeled with optimal descriptors based on the Simplified Molecular Input‐Line Entry System (SMILES). The concentrations of protein‐bound drug for 87 penicillins expressed as percentage of the total plasma concentration were used as experimental data. The Monte Carlo method was used as a computational tool to build up the quantitative structure–activity relationship (QSAR) model for penicillins binding to plasma proteins. One random data split into training, test and validation set was examined. The calculated QSAR model had the following statistical parameters: r2 = 0.8760, q2 = 0.8665, s = 8.94 for the training set and r2 = 0.9812, q2 = 0.9753, s = 7.31 for the test set. For the validation set, the statistical parameters were r2 = 0.727 and s = 12.52, but after removing the three worst outliers, the statistical parameters improved to r2 = 0.921 and s = 7.18. SMILES‐based molecular fragments (structural indicators) responsible for the increase and decrease of penicillins binding to plasma proteins were identified. The possibility of using these results for the computer‐aided design of new penicillins with desired binding properties is presented.

Two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones as new non-purine xanthine oxidase inhibitors and anti-inflammatory agents

Two cyclodidepsipeptides, 3-(2-methylpropyl)-6-(propan-2-yl)-4-methyl-morpholine-2,5-dione (1) and 3,6-di(propan-2-yl)-4-methyl-morpholine-2,5-dione (2), were evaluated for inhibitory activity against commercial enzyme xanthine oxidase (XO) in vitro and XO in rat liver homogenate as well as for anti-inflammatory response on human peripheral blood mononuclear cells (PBMCs). Both of cyclodidepsipeptides were excellent inhibitors of XO and significantly suppressed the nuclear factor of κB (NF-κB) activation. Allopurinol, a widely used XO inhibitor and drug to treat gout, relevated stronger inhibitory effect on rat liver XO activity than those of compounds 1 and 2. Molecular docking studies were performed to gain an insight into their binding modes with XO. The studied morpholine-diones derivatives exerting XO inhibition and anti-inflammatory effect may give a promise to be used in the treatment of gout and other excessive uric acid production or inflammatory conditions.

In silico prediction of the β-cyclodextrin complexation based on Monte Carlo method.

In this study QSPR models were developed to predict the complexation of structurally diverse compounds with β-cyclodextrin based on SMILES notation optimal descriptors using Monte Carlo method. The predictive potential of the applied approach was tested with three random splits into the sub-training, calibration, test and validation sets and with different statistical methods. Obtained results demonstrate that Monte Carlo method based modeling is a very promising computational method in the QSPR studies for predicting the complexation of structurally diverse compounds with β-cyclodextrin. The SMILES attributes (structural features both local and global), defined as molecular fragments, which are promoters of the increase/decrease of molecular binding constants were identified. These structural features were correlated to the complexation process and their identification helped to improve the understanding for the complexation mechanisms of the host molecules.

Spectrophotometric Study of Catechol Oxidation by Aerial O2 in Alkaline Aqueous Solutions Containing Mg(II) Ions.

Abstract Electronic absorption spectroscopy was employed to study the aerial oxidation of catechol (1,2-benzenediol) in alkaline aqueous solution containing an excess of Mg(II) ions. Graphical analysis by the matrix method of UV spectra recorded at regular time intervals gave a good fit for two absorbing species in solution. Based on this result and our earlier ESR spectroscopic investigations we concluded that two main absorbing species in this system are Mg(II)-spin stabilized o-benzosemiquinone anion radical and C-C dimer formed by the nucleophilic attack of catecholate anion on o-benzoquinone. Although the formation of 1,2,4-benzenetriol during the catechol oxidation has been detected in some ESR studies its presence was not indicated by this analysis probably because of the low and/or stable steady state concentration throughout the experiment.

Monte Carlo method based QSAR modeling of maleimide derivatives as glycogen synthase kinase-3β inhibitors

The Monte Carlo method was used for QSAR modeling of maleimide derivatives as glycogen synthase kinase-3β inhibitors. The first QSAR model was developed for a series of 74 3-anilino-4-arylmaleimide derivatives. The second QSAR model was developed for a series of 177 maleimide derivatives. QSAR models were calculated with the representation of the molecular structure by the simplified molecular input-line entry system. Two splits have been examined: one split into the training and test set for the first QSAR model, and one split into the training, test and validation set for the second. The statistical quality of the developed model is very good. The calculated model for 3-anilino-4-arylmaleimide derivatives had following statistical parameters: r(2)=0.8617 for the training set; r(2)=0.8659, and r(m)(2)=0.7361 for the test set. The calculated model for maleimide derivatives had following statistical parameters: r(2)=0.9435, for the training, r(2)=0.9262 and r(m)(2)=0.8199 for the test and r(2)=0.8418, r(av)(m)(2)=0.7469 and ∆r(m)(2)=0.1476 for the validation set. Structural indicators considered as molecular fragments responsible for the increase and decrease in the inhibition activity have been defined. The computer-aided design of new potential glycogen synthase kinase-3β inhibitors has been presented by using defined structural alerts.