The coefficient of conformism of a correlative prediction (CCCP): Building up reliable nano-QSPRs/QSARs for endpoints of nanoparticles in different experimental conditions encoded via quasi-SMILES.

Simulation of the physicochemical and biochemical behavior of nanomaterials has its own specifics. However, the main goal of modeling for both traditional substances and nanomaterials is the same. This is an ecologic risk assessment. The universal indicator of toxicity is the n-octanol/water partition coefficient. Mutagenicity indicates the possibility of future undesirable environmental effects, possibly greater than toxicity. Models have been proposed for the octanol/water distribution coefficient of gold nanoparticles and the mutagenicity of silver nanoparticles. Unlike the previous studies, here the models are built using an updated scheme, which includes two improvements. Firstly, the computing involves a new criterion for prediction potential, the so-called coefficient of conformism of a correlative prediction (CCCP); secondly, the Las Vegas algorithm is used to select the potentially most promising models from a group of models obtained by the Monte Carlo algorithm. Apparently, CCCP is a measure of the predictive potential (not only correlation). This can give an advantage in developing a model in comparison to using the classic determination coefficient. Likely, CCCP can be more informative than the classical determination coefficient. The Las Vegas algorithm is able to improve the model obtained by the Monte Carlo method.

Does the accounting of the local symmetry fragments in quasi-SMILES improve the predictive potential of the QSAR models of toxicity toward tadpoles?

Models of toxicity to tadpoles have been developed as single parameters based on special descriptors which are sums of correlation weights, molecular features, and experimental conditions. This information is presented by quasi-SMILES. Fragments of local symmetry (FLS) are involved in the development of the model and the use of FLS correlation weights improves their predictive potential. In addition, the index of ideality correlation (IIC) and correlation intensity index (CII) are compared. These two potential predictive criteria were tested in models built through Monte Carlo optimization. The CII was more effective than IIC for the models considered here.

Semi-Correlations for Building Up a Simulation of Eye Irritation.

The OECD recognizes that data on a compound's ability to treat eye irritation are essential for the assessment of new compounds on the market. In silico models are frequently used to provide information when experimental data are lacking. Semi-correlations, as they are called, can be useful to build up categorical models for eye irritation. Semi-correlations are latent regressions that can be used when the endpoint is expressed by two values: 1 for an active molecule and 0 for an inactive molecule. The regression line is based on the descriptor values which serve to distribute the data into four classes: true positive, true negative, false positive, and false negative. These values are applied to calculate the corresponding statistical criterion for assessing the predictive potential of the categorical model. In our model, the descriptor is the sum of what are termed correlation weights. These are defined by optimization using the Monte Carlo method. The target function of the optimization is related to the determination coefficient and the mean absolute error for the training set. Our model gives results that are better than those previously reported for the same endpoint.

The System of Self-Consistent Models: The Case of Henry's Law Constants.

Data on Henry's law constants make it possible to systematize geochemical conditions affecting atmosphere status and consequently triggering climate changes. The constants of Henry's law are desired for assessing the processes related to atmospheric contaminations caused by pollutants. The most important are those that are capable of long-term movements over long distances. This ability is closely related to the values of Henry's law constants. Chemical changes in gaseous mixtures affect the fate of atmospheric pollutants and ecology, climate, and human health. Since the number of organic compounds present in the atmosphere is extremely large, it is desirable to develop models suitable for predictions for the large pool of organic molecules that may be present in the atmosphere. Here, we report the development of such a model for Henry's law constants predictions of 29,439 compounds using the CORAL software (2023). The statistical quality of the model is characterized by the value of the coefficient of determination for the training and validation sets of about 0.81 (on average).

Cheminformatics and Machine Learning Approaches to Assess Aquatic Toxicity Profiles of Fullerene Derivatives.

Fullerene derivatives (FDs) are widely used in nanomaterials production, the pharmaceutical industry and biomedicine. In the present study, we focused on the potential toxic effects of FDs on the aquatic environment. First, we analyzed the binding affinity of 169 FDs to 10 human proteins (1D6U, 1E3K, 1GOS, 1GS4, 1H82, 1OG5, 1UOM, 2F9Q, 2J0D, 3ERT) obtained from the Protein Data Bank (PDB) and showing high similarity to proteins from aquatic species. Then, the binding activity of 169 FDs to the enzyme acetylcholinesterase (AChE)-as a known target of toxins in fathead minnows and Daphnia magna, causing the inhibition of AChE-was analyzed. Finally, the structural aquatic toxicity alerts obtained from ToxAlert were used to confirm the possible mechanism of action. Machine learning and cheminformatics tools were used to analyze the data. Counter-propagation artificial neural network (CPANN) models were used to determine key binding properties of FDs to proteins associated with aquatic toxicity. Predicting the binding affinity of unknown FDs using quantitative structure-activity relationship (QSAR) models eliminates the need for complex and time-consuming calculations. The results of the study show which structural features of FDs have the greatest impact on aquatic organisms and help prioritize FDs and make manufacturing decisions.

In silico prediction of the mutagenicity of nitroaromatic compounds using correlation weights of fragments of local symmetry.

Most quantitative structure-property/activity relationships (QSPRs/QSARs) techniques involve using different programs separately for generating molecular descriptors and separately for building models based on available descriptors. Here, the capabilities of the CORAL program are evaluated. A user of the program should apply as the basis for models the representation of the molecular structure by means of the simplified molecular input-line entry system (SMILES) as well as experimental data on the endpoint of interest. The local symmetry of SMILES is a novel composition of symmetrically represented symbols, which are three 'xyx', four 'xyyx', or five symbols 'xyzyx'. We updated our CORAL software using this optimal, new flexible descriptor, sensitive to the symmetric composition of a specific part of the molecule. Computational experiments have shown that taking account of these attributes of SMILES can improve the predictive potential of models for the mutagenicity of nitroaromatic compounds. In addition, the above computational experiments have confirmed the advantage of using the index of ideality of correlation (IIC) and the correlation intensity index (CII) for Monte Carlo optimization of the correlation weights for various attributes of SMILES, including the local symmetry. The average value of the coefficient of determination for the validation set (five different models) without fragments of local symmetry is 0.8589 ± 0.025, whereas using fragments of local symmetry improves this criterion of the predictive potential up to 0.9055 ± 0.010.

Using the Correlation Intensity Index to Build a Model of Cardiotoxicity of Piperidine Derivatives.

The assessment of cardiotoxicity is a persistent problem in medicinal chemistry. Quantitative structure-activity relationships (QSAR) are one possible way to build up models for cardiotoxicity. Here, we describe the results obtained with the Monte Carlo technique to develop hybrid optimal descriptors correlated with cardiotoxicity. The predictive potential of the cardiotoxicity models (pIC50, Ki in nM) of piperidine derivatives obtained using this approach provided quite good determination coefficients for the external validation set, in the range of 0.90-0.94. The results were best when applying the so-called correlation intensity index, which improves the predictive potential of a model.

Using the local symmetry in amino acids sequences of polypeptides to improve the predictive potential of models of their inhibitor activity.

The minimal inhibitory concentrations (pMIC) are a valuable measure of the biological activity of polypeptides. Numerical data on the pMIC are necessary to systematize knowledge on polypeptides' biochemical behaviour. The model of negative decimal logarithm of pMIC of polypeptides in the form of a mathematical function of a sequence of amino acids is suggested. The suggested model is based on the so-called correlation weights of amino acids together with the correlation weights of fragments of local symmetry (FLS). Three kinds of the FLS are considered: (i) three-symbol fragments '…xyx…', (ii) four-symbol fragments '…xyyx…', and (iii) five-symbol fragments '…xyzyx…'. The models built using the Monte Carlo technique improved by applying the index of ideality of correlation (IIC) and correlation intensity index (CII).

The enhancement scheme for the predictive ability of QSAR: A case of mutagenicity.

Mutagenicity is one of the most dangerous properties from the point of view of medicine and ecology. Experimental determination of mutagenicity remains a costly process, which makes it attractive to identify new hazardous compounds based on available experimental data through in silico methods or quantitative structure-activity relationships (QSAR). A system for constructing groups of random models is proposed for comparing various molecular features extracted from SMILES and graphs. For mutagenicity (mutagenicity values were expressed by the logarithm of the number of revertants per nanomole assayed by Salmonella typhimurium TA98-S9 microsomal preparation) models, the Morgan connectivity values are more informative than the comparison of quality for different rings in molecules. The resulting models were tested with the previously proposed model self-consistency system. The average determination coefficient for the validation set is 0.8737 ± 0.0312.

Development of Self-Consistency Models of Anticancer Activity of Nanoparticles under Different Experimental Conditions Using Quasi-SMILES Approach.

Algorithms of the simulation of the anticancer activity of nanoparticles under different experimental conditions toward cell lines A549 (lung cancer), THP-1 (leukemia), MCF-7 (breast cancer), Caco2 (cervical cancer), and hepG2 (hepatoma) have been developed using the quasi-SMILES approach. This approach is suggested as an efficient tool for the quantitative structure-property-activity relationships (QSPRs/QSARs) analysis of the above nanoparticles. The studied model is built up using the so-called vector of ideality of correlation. The components of this vector include the index of ideality of correlation (IIC) and the correlation intensity index (CII). The epistemological component of this study is the development of methods of registration, storage, and effective use of experimental situations that are comfortable for the researcher-experimentalist in order to be able to control the physicochemical and biochemical consequences of using nanomaterials. The proposed approach differs from the traditional models based on QSPR/QSAR in the following respects: (i) not molecules but experimental situations available in a database are considered; in other words, an answer is offered to the question of how to change the plot of the experiment in order to achieve the desired values of the endpoint being studied; and (ii) the user has the ability to select a list of controlled conditions available in the database that can affect the endpoint and evaluate how significant the influence of the selected controlled experimental conditions is.

The validation of predictive potential via the system of self-consistent models: the simulation of blood-brain barrier permeation of organic compounds.

CONTEXT: To apply the quantitative relationships "structure-endpoint" approach, the reliability of prediction is necessary but sometimes challenging to achieve. In this work, an attempt is made to accomplish the reliability of forecasts by creating a set of random partitions of data into training and validation sets, followed by constructing random models. A system of random models for a helpful approach should be self-consistent, giving a similar or at least comparable statistical quality of the predictions for models obtained using different splits of available data into training and validation sets. METHOD: The carried out computer experiments aimed at obtaining blood-brain barrier permeation models showed that, in principle, can be used such an approach (the Monte Carlo optimization of the correlation weights for different molecular features) for the above purpose taking advantage of specific algorithms to optimize the modelling steps with applying of new statistical criteria such as the index of ideality of correlation (IIC) and the correlation intensity index (CII). The results so obtained are good and better than what was reported previously. The suggested approach to validation of models is non-identic to traditionally applied manners of the checking up models. The concept of validation can be used for arbitrary models (not only for models of the blood-brain barrier).

CORAL: Model of Ecological Impact of Heavy Metals on Soils via the Study of Modification of Concentration of Biomolecules in Earthworms (Eisenia fetida).

The traditional application for quantitative structure-property/activity relationships (QSPRs/QSARs) in the fields of thermodynamics, toxicology or drug design is predicting the impact of molecular features using data on the measurable characteristics of substances. However, it is often necessary to evaluate the influence of various exposure conditions and environmental factors, besides the molecular structure. Different enzyme-driven processes lead to the accumulation of metal ions by the worms. Heavy metals are sequestered in these organisms without being released back into the soil. In this study, we propose a novel approach for modeling the absorption of heavy metals, such as mercury and cobalt by worms. The models are based on optimal descriptors calculated for the so-called quasi-SMILES, which incorporate strings of codes reflecting experimental conditions. We modeled the impact on the levels of proteins, hydrocarbons, and lipids in an earthworm's body caused by different combinations of concentrations of heavy metals and exposure time observed over two months of exposure with a measurement interval of 15 days.

The System of Self-Consistent Models: QSAR Analysis of Drug-Induced Liver Toxicity.

Removing a drug-like substance that can cause drug-induced liver injury from the drug discovery process is a significant task for medicinal chemistry. In silico models can facilitate this process. Semi-correlation is an approach to building in silico models representing the prediction in the active (1)-inactive (0) format. The so-called system of self-consistent models has been suggested as an approach for two tasks: (i) building up a model and (ii) estimating its predictive potential. However, this approach has been tested so far for regression models. Here, the approach is applied to building up and estimating a categorical hepatotoxicity model using the CORAL software. This new process yields good results: sensitivity = 0.77, specificity = 0.75, accuracy = 0.76, and Matthew correlation coefficient = 0.51 (all compounds) and sensitivity = 0.83, specificity = 0.81, accuracy = 0.83 and Matthew correlation coefficient = 0.63 (validation set).

A Nano-QSTR model to predict nano-cytotoxicity: an approach using human lung cells data.

BACKGROUND: The widespread use of new engineered nanomaterials (ENMs) in industries such as cosmetics, electronics, and diagnostic nanodevices, has been revolutionizing our society. However, emerging studies suggest that ENMs present potentially toxic effects on the human lung. In this regard, we developed a machine learning (ML) nano-quantitative-structure-toxicity relationship (QSTR) model to predict the potential human lung nano-cytotoxicity induced by exposure to ENMs based on metal oxide nanoparticles. RESULTS: Tree-based learning algorithms (e.g., decision tree (DT), random forest (RF), and extra-trees (ET)) were able to predict ENMs' cytotoxic risk in an efficient, robust, and interpretable way. The best-ranked ET nano-QSTR model showed excellent statistical performance with R2 and Q2-based metrics of 0.95, 0.80, and 0.79 for training, internal validation, and external validation subsets, respectively. Several nano-descriptors linked to the core-type and surface coating reactivity properties were identified as the most relevant characteristics to predict human lung nano-cytotoxicity. CONCLUSIONS: The proposed model suggests that a decrease in the ENMs diameter could significantly increase their potential ability to access lung subcellular compartments (e.g., mitochondria and nuclei), promoting strong nano-cytotoxicity and epithelial barrier dysfunction. Additionally, the presence of polyethylene glycol (PEG) as a surface coating could prevent the potential release of cytotoxic metal ions, promoting lung cytoprotection. Overall, the current work could pave the way for efficient decision-making, prediction, and mitigation of the potential occupational and environmental ENMs risks.

CORAL Models for Drug-Induced Nephrotoxicity.

Drug-induced nephrotoxicity is a major cause of kidney dysfunction with potentially fatal consequences. The poor prediction of clinical responses based on preclinical research hampers the development of new pharmaceuticals. This emphasises the need for new methods for earlier and more accurate diagnosis to avoid drug-induced kidney injuries. Computational predictions of drug-induced nephrotoxicity are an attractive approach to facilitate such an assessment and such models could serve as robust and reliable replacements for animal testing. To provide the chemical information for computational prediction, we used the convenient and common SMILES format. We examined several versions of so-called optimal SMILES-based descriptors. We obtained the highest statistical values, considering the specificity, sensitivity and accuracy of the prediction, by applying recently suggested atoms pairs proportions vectors and the index of ideality of correlation, which is a special statistical measure of the predictive potential. Implementation of this tool in the drug development process might lead to safer drugs in the future.

Machine-learning technique, QSAR and molecular dynamics for hERG-drug interactions.

One of the most well-known anti-targets defining medication cardiotoxicity is the voltage-dependent hERG K + channel, which is well-known for its crucial involvement in cardiac action potential repolarization. Torsades de Pointes, QT prolongation, and sudden death are all caused by hERG (the human Ether-à-go-go-Related Gene) inhibition. There is great interest in creating predictive computational (in silico) tools to identify and weed out potential hERG blockers early in the drug discovery process because testing for hERG liability and the traditional experimental screening are complicated, expensive and time-consuming. This study used 2D descriptors of a large curated dataset of 6766 compounds and machine learning approaches to build robust descriptor-based QSAR and predictive classification models for KCNH2 liability. Decision Tree, Random Forest, Logistic Regression, Ada Boosting, kNN, SVM, Naïve Bayes, neural network and stochastic gradient classification classifier algorithms were used to build classification models. If a compound's IC50 value was between 10 µM and less, it was classified as a blocker (hERG-positive), and if it was more, it was classified as a non-blocker (hERG-negative). Matthew's correlation coefficient formula and F1score were applied to compare and track the developed models' performance. Molecular docking and dynamics studies were performed to understand the cardiotoxicity relating to the hERG-gene. The hERG residues interacting after 100 ns are LEU:697, THR:708, PHE:656, HIS:674, HIS:703, TRP:705 and ASN:709 and the hERG-ligand-16 complex trajectory showed stable behaviour with lesser fluctuations in the entire simulation of 200 ns.Communicated by Ramaswamy H. Sarma.

The system of self-consistent models for pesticide toxicity to Daphnia magna.

Quantitative structure-property/activity relationships (QSPRs/QSARs) are a tool of modern theoretical and computational chemistry. The self-consistent model system is both a method to build up a group of QSPR/QSAR models and an approach to checking the reliability of these models. Here, a group of models of pesticide toxicity toward Daphnia magna for different distributions into training and test sub-sets is compared. This comparison is the basis for formulating the system of self-consistent models. The so-called index of the ideality of correlation (IIC) has been used to improve the above models' predictive potential of pesticide toxicity. The predictive potential of the suggested models should be classified as high since the average value of the determination coefficient for the validation sets is 0.841, and the dispersion is 0.033 (on all five models). The best model (number 4) has an average determination coefficient of 0.89 for the external validation sets (related to all five splits).

The system of self-consistent models based on quasi-SMILES as a tool to predict the potential of nano-inhibitors of human lung carcinoma cell line A549 for different experimental conditions.

The different features of the impact of nanoparticles on cells, such as the structure of the core, presence/absence of doping, quality of surface, diameter, and dose, were used to define quasi-SMILES, a line of symbols encoded the above physicochemical features of the impact of nanoparticles. The correlation weight for each code in the quasi-SMILES has been calculated by the Monte Carlo method. The descriptor, which is the sum of the correlation weights, is the basis for a one-variable model of the biological activity of nano-inhibitors of human lung carcinoma cell line A549. The system of models obtained by the above scheme was checked on the self-consistence, i.e., reproducing the statistical quality of these models observed for different distributions of available nanomaterials into the training and validation sets. The computational experiments confirm the excellent potential of the approach as a tool to predict the impact of nanomaterials under different experimental conditions. In conclusion, our model is a self-consistent model system that provides a user to assess the reliability of the statistical quality of the used approach.

In Silico Simulation of Impacts of Metal Nano-Oxides on Cell Viability in THP-1 Cells Based on the Correlation Weights of the Fragments of Molecular Structures and Codes of Experimental Conditions Represented by Means of Quasi-SMILES.

A simulation of the effect of metal nano-oxides at various concentrations (25, 50, 100, and 200 milligrams per millilitre) on cell viability in THP-1 cells (%) based on data on the molecular structure of the oxide and its concentration is proposed. We used a simplified molecular input-line entry system (SMILES) to represent the molecular structure. So-called quasi-SMILES extends usual SMILES with special codes for experimental conditions (concentration). The approach based on building up models using quasi-SMILES is self-consistent, i.e., the predictive potential of the model group obtained by random splits into training and validation sets is stable. The Monte Carlo method was used as a basis for building up the above groups of models. The CORAL software was applied to building the Monte Carlo calculations. The average determination coefficient for the five different validation sets was R2 = 0.806 ± 0.061.

Quasi-SMILES as a basis to build up models of endpoints for nanomaterials.

Simplified molecular input-line entry system (SMILES) is a format for representing of the molecular structure. Quasi-SMILES is an extended format for representing molecular structure data and some eclectic data, which in principle could be applied to improve a model's predictive potential. Nano-quantitative structure-property relationships (nano-QSPRs) for energy gap (Eg, eV) of the metals oxide nanoparticles based on the quasi-SMILES give a predictive model for Eg, characterized by the following statistical quality for external validation set n = 22, R2 = 0.83, RMSE = 0.267.