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Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising dual-targeting inhibitors in cancer and neurodegenerative diseases treatment. Data fusion of receptor-based and ligand-based information of dual IDO1/TDO inhibitors were employed for active/inactive classification performance. A reliable decision making procedure was used here to identify active/inactive dual IDO1/TDO inhibitors using majority voting method and pools of individual classifications instead of individual models. All classification models were validated using prediction set, cross-validation and y-scrambling tests. The classification outcomes indicate that the sensitivity, specificity, precision, accuracy, G-mean and F1 score values increases up to ∼90% using data fusion and majority voting method. Compare to individual classification models with a single prediction point, the majority voting method has more reliable results due to the integration of the pool of individual classification models. This classification strategy may lead to more reliable identification of active/inactive dual-targeting inhibitors in cancer immunotherapy.Communicated by Ramaswamy H. Sarma.

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A novel decision-making procedure is proposed here for the first time to identify active/inactive and selective/non-selective dual inhibitors using consensus approaches and pools of k-nearest neighbours (kNN) classifications instead of individual models. Dual BRD4/PLK1 inhibition with adequate selectivity is a potential therapeutic strategy for targeting tumour cells in high-risk patients. We report the unique way to identify both active and selective dual BRD4/PLK1 inhibitors using consensus and kNN strategies together with two sources of receptor-based and ligand-based information which are the ranked binding energies of residues and important molecular features, respectively. The results of consensus approaches were compared with the results of individual kNN models. The chemical space similarity was measured using three different distance functions to increase the reliability. All activity and selectivity classification models were validated using cross-validation and y-randomization tests. The outcomes show that consensus approaches can increase the reliability and accuracy of active/inactive or selective/non-selective detections up to 90%. Consensus approaches also reached more balanced values of sensitivity and specificity compared to the individual kNN models because of the compensation in the integration of diverse sources of information.

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The idea of using ranked binding energies of residues and data fusion are presented here for the first time as a valuable tool to classify active and selective inhibitors. Selective inhibitors of JAK3 can inhibit inflammatory cytokine while preventing targeting other subtypes of JAK1 and JAK2. Herein, we report a novel way to identify both active JAK3 and selective JAK1/JAK3 and JAK2/JAK3 inhibitors using the effective activity and selectivity classifications. The most important residues (top 10) responsible for the inhibition mechanism are sorted from high to low energies, which are considered as variables in the classification process. In addition, the ranked energies of ligands' heteroatoms (top 5), ranked energies of hydrogen bonds (top 5) and important molecular descriptors (top 10) were used to construct different data fusion possibilities. It is shown that the proposed data fusion strategy can increase the accuracy of the activity classification to 100% and the selectivity classification to 96.4%. The proposed strategies represented in this paper can help medicinal or pharmaceutical chemist in evaluation of both active and selective inhibitors before synthesizing new pharmaceuticals.

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Pim kinase enzyme has an essential role in the treatment of prostate, colon and acute myeloid leukaemia cancers. The indoles inhibitors were docked in the enzyme's active pocket in order to survey the inhibition mechanism and extract the ligands' conformations. The docking outcome shows that the active inhibitors have strong van der Waals interactions with residues of Ile185, Leu44, Leu120 and Leu174, hydrogen bonds with residues of Asp128, Arg122 and Glu171 and π-π interaction with the residue of Phe49. The sum of these interactions is ~80 kcal mol-1 contributing ~90% of total binding free energies. Using docking-based molecular descriptors, the unsupervised and supervised classifications were successfully carried out with the accuracy of 0.82 and 0.95, respectively, to categorize the active/inactive Pim kinase inhibitors. The vigorous quantitative assessment was performed using different machine learning techniques. The constructed QSAR model [(r 2 cal, r 2 p, r 2 m and Q 2 LOO) > 0.80 and (SE cal, SEp and SE LOO) < 0.22] indicates that the molecular descriptors of nN, RDF20v and E1v can describe both the inhibition activities and the inhibition mechanism. The adequate evaluations of the molecular docking, classifications and QSAR analysis show that the current approaches can be used as valuable tools to design more effective new Pim kinase inhibitors for cancer treatment.

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The α-glucosidase inhibitors are considered as important agents in drug discovery against diabetes mellitus. Molecular docking and quantitative structure-activity relationship (QSAR) were performed based on a series of tetracyclic oxindole derivatives to elucidate key structural properties affecting inhibitory activity and support the design of new α-glucosidase inhibitors. The molecular docking results demonstrate that at least two hydrogen bonds between Thr681 and Arg676 residues and the oxygen atoms in amid groups have an important role in the optimum binding of inhibitors. In addition, the sum of polar contacts of Arg699, Arg670, Glu792 and Glu301 residues with the α-glucosidase inhibitors have more than one third of total binding free energy. The docked conformations of the inhibitors with the best binding free energy were used to construct QSAR models. As a primary survey and a graphical comparing tool, the partial least squares-discriminant analysis (PLS-DA) technique was successfully employed to classify active and inactive inhibitors. The validated QSAR analysis were performed through genetic algorithm-partial least squares (GA-PLS) and support vector machine (SVM) techniques. The QSAR model reveals that important features of J3D, Mor26 u and HOMA have a high predictive capability (R2p = 0.837, Q2LOO = 0.871, R2LSO = 0.790 and r2m = 0.758) using GA-PLS/SVM strategy. Generally, the suggested QSAR analysis based on classification, docking and GA-PLS/SVM strategy may help suggest chemical scaffold to design novel oxindole derivatives as α-glucosidase inhibitors.

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Mutated epidermal growth factor receptor (EGFR-T790M) inhibitors hold promise as new agents against cancer. Molecular docking and QSAR analysis were performed based on a series of fifty-three quinazoline derivatives to elucidate key structural and physicochemical properties affecting inhibitory activity. Molecular docking analysis identified the true conformations of ligands in the receptor's active pocket. The structural features of the ligands, expressed as molecular descriptors, were derived from the obtained docked conformations. Non-linear and spline QSAR models were developed through novel genetic algorithm and artificial neural network (GA-ANN) and multivariate adaptive regression spline techniques, respectively. The former technique was employed to consider non-linear relation between molecular descriptors and inhibitory activity of quinazoline derivatives. The later technique was also used to describe the non-linearity using basis functions and sub-region equations for each descriptor. Our QSAR model gave a high predictive performance [Formula: see text] and [Formula: see text]) using diverse validation techniques. Eight new compounds were designed using our QSAR model as potent EGFR-T790M inhibitors. Overall, the proposed in silico strategy based on docked derived descriptor and non-linear descriptor subset selection may help design novel quinazoline derivatives with improved EGFR-T790M inhibitory activity.

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The main idea of this study was to find predictive quantitative structure-activity relationships (QSAR) for the therapeutic index of 68 thiazolidin-4-one analogs against Toxoplasma gondii. Multivariate adaptive regression spline (MARS) together with Monte-Carlo (MC) sampling was proposed as a reliable descriptor subset selection strategy. Basis functions and knot points are also determined for each selected descriptor using generalized cross validation after frequency analysis. Least squares-support vector regression (LS-SVR) with optimized hyper-parameters was employed as mapping tool due to its promising empirical performance. The models were validated and tested through the use of the external prediction set of compounds, leave-one-out and leave-many-out cross validation methods, applicability domain analysis and Y-randomization. The robustness and accuracy of the QSAR models were confirmed by the satisfactory statistical parameters for the experimentally reported dataset (R(2)p=0.853, Q(2)LOO=0.785, R(2)L20%O=0.742 and r(2)m=0.715) and low standard error values (RMSEp=0.208, RMSELOO=0.321 and RMSEL20%O=0.376). The comprehensive analysis carried out in the present contribution using the proposed strategy can provide a considerable basis for the design and development of novel drug-like molecules against T.gondii.

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Aldehydes are toxic environmental contaminants which cause severe health hazards. There is a growing need by industries and regulatory agencies for the development of tools able to assess the potential hazardous effects of chemicals on living organisms. In this background, multivariate image analysis combined with quantitative structure-toxicity relationships (MIA-QSTR) was used to evaluate the toxicity of aromatic aldehydes to Tetrahymena pyriformis. The techniques of genetic algorithm-partial least squares (GA-PLS) were applied effectively as MIA descriptor selection and mapping tools. In MIA-QSTR evaluation, pixels of 2D images of chemical structures could be used to recognize physicochemical information and predict changes in the toxicities. The resulting MIA-QSTR explains 90.3% leave-one-out predicted variance and 93.1% external predicted variance. The MIA-QSTR/GA-PLS performances were validated using various evaluation techniques such as cross-validation, applicability domain and Y-scrambling procedures, suggesting that the present methodology together with mechanistic interpretation may be useful to evaluate toxicity, safety and risk assessment of toxic environmental contaminants.

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The widespread production of esters combined with their ability to migrate in different compartments, makes their environmental toxicity important. In this background, the multivariate image analysis-quantitative structure-toxicity relationship (MIA-QSTR) method coupled to principal component analysis-adaptive neuro-fuzzy inference systems (PCA-ANFIS) was applied to assess the toxicity of esters to Daphnia magna. In MIA-QSTR, pixels of chemical structures (2D images) stand for descriptors, and structural changes account for the variance in toxicities. The ANFIS procedure was capable of correlating the inputs (PCA scores) with the toxicities accurately. The PCA-ANFIS also was statistically validated for its predictive power using cross-validation, applicability domain and Y-scrambling evaluation procedures. The satisfactory results (R p (2) = 0.926, Q LOO (2) = 0.887, R L25%O (2) = 0.843, RMSELOO = 0.320 and RMSEL25%O = 0.379) suggests that the QSTR model could be proposed as an alternative method for aquatic toxicity assessment of esters allowing possible application in the European Union regulation REACH.

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There is an increasing need for the rapid safety assessment of chemicals by both industries and regulatory agencies throughout the world. In silico techniques are practical alternatives in the environmental hazard assessment. In this background, quantitative structure-toxicity relationship (QSTR) analysis has been performed on toxicity of phenols and thiophenols to Photobacterium phosphoreum. The techniques of classification and regression trees (CART) and least squares support vector regressions (LS-SVR) were applied successfully as variable selection and mapping tools, respectively. Four descriptors selected by the CART technique have been used as inputs of the LS-SVR for prediction of toxicities. The best model explains 91.8% leave-one-out predicted variance and 93.0% external predicted variance. The predictive performance of the CART-LS-SVR model was significantly better than the previous reported models based on CoMFA/CoMSIA and stepwise MLR techniques, suggesting that the present methodology may be useful to predict of toxicity, safety and risk assessment of chemicals.

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The present work focuses on the development of an interpretable quantitative structure-activity relationship (QSAR) model for predicting the anti-HIV activities of 67 thiazolylthiourea derivatives. This set of molecules has been proposed as potent HIV-1 reverse transcriptase inhibitors (RT-INs). The molecules were encoded to a diverse set of molecular descriptors, spanning different physical and chemical properties. Monte Carlo (MC) sampling and multivariate adaptive regression spline (MARS) techniques were used to select the most important descriptors and to predict the activity of the molecules. The most important descriptor was found to be the aspherisity index. The analysis of variance (ANOVA) and interpretable spline equations showed that the geometrical shape of the molecules has considerable effect on their activities. It seems that the linear molecules are more active than symmetric top compounds. The final MARS model derived displayed a good predictive ability judging from the determination coefficient corresponding to the leave multiple out (LMO) cross-validation technique, i.e. r (2 )= 0.828 (M = 12) and r (2 )= 0.813 (M = 20). The results of this work showed that the developed spline model is robust, has a good predictive power, and can then be used as a reliable tool for designing novel HIV-1 RT-INs.

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The purpose of this study was to develop quantitative structure-activity relationship models for N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. These models were developed with the aid of classification and regression trees (CART) and an adaptive neuro-fuzzy inference system (ANFIS) combined with a shuffling cross-validation technique using interpretable descriptors. More than one hundred meaningful descriptors, representing various structural characteristics for all 51 N-benzoylindazole derivatives in the data set, were calculated and used as the original variables for shuffling CART modelling. Five descriptors of average Wiener index, Kier benzene-likeliness index, subpolarity parameter, average shape profile index of order 2 and folding degree index selected by the shuffling CART technique have been used as inputs of the ANFIS for prediction of inhibition behaviour of N-benzoylindazole derivatives. The results of the developed shuffling CART-ANFIS model compared to other techniques, such as genetic algorithm (GA)-partial least square (PLS)-ANFIS and stepwise multiple linear regression (MLR)-ANFIS, are promising and descriptive. The satisfactory results r2p = 0.845, Q2(LOO) = 0.861, r2(L25%O) = 0.829, RMSE(LOO) = 0.305 and RMSE(L25%O) = 0.336) demonstrate that shuffling CART-ANFIS models present the relationship between human neutrophil elastase inhibitor activity and molecular descriptors, and they yield predictions in excellent agreement with the experimental values.

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In this work, the inhibitory activity of pyridine N-oxide derivatives against human severe acute respiratory syndrome (SARS) is predicted in terms of quantitative structure-activity relationship (QSAR) models. These models were developed with the aid of multivariate adaptive regression spline (MARS) and adaptive neuro-fuzzy inference system (ANFIS) combined with shuffling cross-validation technique. A shuffling MARS algorithm is utilized to select the most important variables in QSAR modeling and then these variables were used as inputs of ANFIS to predict SARS inhibitory activities of pyridine N-oxide derivatives. A data set of 119 drug-like compounds was coded with over hundred calculated meaningful molecular descriptors. The best descriptors describing the inhibition mechanism were solvation connectivity index, length to breadth ratio, relative negative charge, harmonic oscillator of aromatic index, average molecular weight and total path count. These parameters are among topological, electronic, geometric, constitutional and aromaticity descriptors. The statistical parameters of R2 and root mean square error (RMSE) are 0.884 and 0.359, respectively. The accuracy and robustness of shuffling MARS-ANFIS model in predicting inhibition behavior of pyridine N-oxide derivatives (pIC50) was illustrated using leave-one-out and leave-multiple-out cross-validation techniques and also by Y-randomization. Comparison of the results of the proposed model with those of GA-PLS-ANFIS shows that the shuffling MARS-ANFIS model is superior and can be considered as a tool for predicting the inhibitory behavior of SARS drug-like molecules.

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Quantitative structure-activity relationship (QSAR) approach was carried out for the prediction of inhibitory activity of some novel quinazolinone derivatives on serotonin (5-HT(7)) using modified ant colony (ACO) method and adaptive neuro-fuzzy interference system (ANFIS) combined with shuffling cross-validation technique. A modified ACO algorithm is utilized to select the most important variables in QSAR modeling and then these variables were used as inputs of ANFIS to predict 5-HT(7) receptor binding activities of quinazolinone derivatives. The best descriptors describing the inhibition mechanism are Q(max), Se, Hy, PJI3 and DELS which are among electronic, constitutional, geometric and empirical descriptors. The statistical parameters of R(2) and root mean square error are 0.775 and 0.360, respectively. The ability and robustness of modified ACO-ANFIS model in predicting inhibition behavior of quinazolinone derivatives (pIC(50)) are illustrated by validation techniques of leave-one-out and leave-multiple-out cross-validations and also by Y-randomization technique. Comparison of the modified ACO-ANFIS method with two other methods, that is, stepwise MLR-ANFIS and GA-PLS-ANFIS were also studied and the results indicated that the proposed model in this work is superior over the others.

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A linear and non-linear quantitative structure-activity relationship (QSAR) study is presented for modeling and predicting heparanase inhibitors' activity. A data set that consisted of 92 derivatives of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid, furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acids is used in this study. Among a large number of descriptors, four parameters classified as physico-chemical, topological and electronic indices are chosen using stepwise multiple regression technique. The artificial neural networks (ANNs) model shows superiority over the multiple linear regressions (MLR) by accounting 87.9% of the variances of antiviral potency of the heparanase inhibitors. This paper focuses on investigating the role of weight update functions in developing ANNs. Levenberg-Marquardt (L-M) algorithm shows a better performance compared with basic back propagation (BBP) and conjugate gradient (CG) algorithms. The accuracy of 4-3-1 L-M ANN model was illustrated using leave-one-out (LOO), leave-multiple-out (LMO) cross-validations and Y-randomization. The mean effect of descriptors and sensitivity analysis show that log P is the most important parameter affecting the inhibitory behavior of the molecules.

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