Modelling of antiproliferative activity measured in HeLa cervical cancer cells in a series of xanthene derivatives.

Cancer remains one of the leading causes of death in humans, and new drug substances are therefore being developed. Thus, the anti-cancer activity of xanthene derivatives has become an important topic in the development of new and potent anti-cancer drug substances. Previously published novel series of xanthen-3-one and xanthen-1,8-dione derivatives have been synthesized in one of our laboratories and showed anti-proliferative activity in HeLa cancer cell lines. This series serves as a good basis to develop quantitative structure-activity relationship (QSAR), to study the relations between anti-proliferative activity and chemical structures. A QSAR model has been derived that relies only on two-dimensional molecular descriptors, providing mechanistic insight into the anti-proliferative activity of xanthene derivatives. The model is validated internally and externally and additionally with the set of inactive compounds of the original data, confirming model applicability for the design and discovery of novel xanthene derivatives. The QSAR model is available at the QsarDB repository (http://dx.doi.10.15152/QDB.237).

Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds.

Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r(2) > 0.8 for pH 3 and pH 5. For basic compounds, the best (r(2) > 0.7) structure-permeability relationships are obtained with the octanol-water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository ( http://dx.doi.org/10.15152/QDB.166 ).

QSAR DataBank repository: open and linked qualitative and quantitative structure-activity relationship models.

BACKGROUND: Structure-activity relationship models have been used to gain insight into chemical and physical processes in biomedicine, toxicology, biotechnology, etc. for almost a century. They have been recognized as valuable tools in decision support workflows for qualitative and quantitative predictions. The main obstacle preventing broader adoption of quantitative structure-activity relationships [(Q)SARs] is that published models are still relatively difficult to discover, retrieve and redeploy in a modern computer-oriented environment. This publication describes a digital repository that makes in silico (Q)SAR-type descriptive and predictive models archivable, citable and usable in a novel way for most common research and applied science purposes. DESCRIPTION: The QSAR DataBank (QsarDB) repository aims to make the processes and outcomes of in silico modelling work transparent, reproducible and accessible. Briefly, the models are represented in the QsarDB data format and stored in a content-aware repository (a.k.a. smart repository). Content awareness has two dimensions. First, models are organized into collections and then into collection hierarchies based on their metadata. Second, the repository is not only an environment for browsing and downloading models (the QDB archive) but also offers integrated services, such as model analysis and visualization and prediction making. CONCLUSIONS: The QsarDB repository unlocks the potential of descriptive and predictive in silico (Q)SAR-type models by allowing new and different types of collaboration between model developers and model users. The key enabling factor is the representation of (Q)SAR models in the QsarDB data format, which makes it easy to preserve and share all relevant data, information and knowledge. Model developers can become more productive by effectively reusing prior art. Model users can make more confident decisions by relying on supporting information that is larger and more diverse than before. Furthermore, the smart repository automates most of the mundane work (e.g., collecting, systematizing, and reporting data), thereby reducing the time to decision.

Classifying bio-concentration factor with random forest algorithm, influence of the bio-accumulative vs. non-bio-accumulative compound ratio to modelling result, and applicability domain for random forest model.

In environmental risk assessment, the bio-concentration factor (BCF) is a widely used parameter in the estimation of the bio-accumulation potential of chemicals. BCF data often have an uneven distribution of classes (bio-accumulative vs. non-bio-accumulative), which could severely bias the classification results towards the prevailing class. The present study focuses on the influence of uneven distribution of the classes in training phase of Random Forest (RF) classification models. Three different training set designs were used and descriptors selected to the models based on the occurrence frequency in RF trees and considering the mechanistic aspects they reflect. Models were compared and their classification performance was analysed, indicating good predictive characteristics (sensitivity = 0.90 and specificity = 0.83) for the balanced set; also imbalanced sets have their strengths in certain application scenarios. The confidence of classifications was assessed with a new schema for the applicability domain that makes use of the RF proximity matrix by analysing the similarity between the predicted compound and the training set of the model. All developed models were made available in the transparent, accessible and reproducible way in QsarDB repository (http://dx.doi.org/10.15152/QDB.116).

Drugs, non-drugs, and disease category specificity: organ effects by ligand pharmacology.

Important understanding can be gained from using molecular biology-based and chemistry-based techniques together. Bayesian classifiers have thus been developed in the present work using several statistically significant molecular properties of compiled datasets of drugs and non-drugs, including their disease category or organ. The results show they provide a useful classification and simplicity of several different ligand efficiencies and molecular properties. Early recall of drugs among non-drugs using the classifiers as a ranking tool is also provided. As the chemical space of compounds is addressed together with their anatomical characterization, chemical libraries can be improved to select for specific organ or disease. Eventually, by including even finer detail, the method may help in designing libraries with specific pharmacological or toxicological target chemical space. Alternatively, a lack of statistically significant differences in property density distributions may help in further describing compounds with possibility of activity on several organs or disease groups, and given their very similar or considerably overlapping chemical space, therefore wanted or unwanted side-effects. The overlaps between densities for several properties of organs or disease categories were calculated by integrating the area under the curves where they intersect. The naïve Bayesian classifiers are readily built, fast to score, and easily interpretable.

Comparative analysis of local and consensus quantitative structure-activity relationship approaches for the prediction of bioconcentration factor.

Quantitative structure-activity relationships (QSARs) are broadly classified as global or local, depending on their molecular constitution. Global models use large and diverse training sets covering a wide range of chemical space. Local models focus on smaller structurally or chemically similar subsets that are conventionally selected by human experts or alternatively using clustering analysis. The current study focuses on the comparative analysis of different clustering algorithms (expectation-maximization, K-means and hierarchical) for seven different descriptor sets as structural characteristics and two rule-based approaches to select subsets for designing local QSAR models. A total of 111 local QSAR models are developed for predicting bioconcentration factor. Predictions from local models were compared with corresponding predictions from the global model. The comparison of coefficients of determination (r(2)) and standard deviations for local models with similar subsets from the global model show improved prediction quality in 97% of cases. The descriptor content of derived QSARs is discussed and analyzed. Local QSAR models were further consolidated within the framework of consensus approach. All different consensus approaches increased performance over the global and local models. The consensus approach reduced the number of strongly deviating predictions by evening out prediction errors, which were produced by some local QSARs.

Molecular property filters describing pharmacokinetics and drug binding.

Drug-target binding affinity and pharmacokinetics are equally important factors of drug design. Simple molecular properties such as molecular size have been used as pharmacokinetic and/or drug-likeness filters during chemical library design and also correlated with binding affinity. In the present study, current property filters are reviewed, a collection of their optimal values is provided, and a statistical framework is introduced allowing calibration of their selectivity and sensitivity for drugs. The role of ligand efficiency indices in drug design is also described. It is concluded that the usefulness of property filters of molecular size and lipophilicity is limited as predictors of general drug-likeness. However, they demonstrate increased performance in specific cases, e.g. in central nervous system diseases, emphasizing their future importance in specific, disease-focused library design instead of general drug-likeness filtering.

Quantitative structure-activity relationship analysis of acute toxicity of diverse chemicals to Daphnia magna with whole molecule descriptors.

Quantitative structure-activity relationship analysis and estimation of toxicological effects at lower-mid trophic levels provide first aid means to understand the toxicity of chemicals. Daphnia magna serves as a good starting point for such toxicity studies and is also recognized for regulatory use in estimating the risk of chemicals. The ECOTOX database was queried and analysed for available data and a homogenous subset of 253 compounds for the endpoint LC50 48 h was established. A four-parameter quantitative structure-activity relationship was derived (coefficient of determination, r (2) = 0.740) for half of the compounds and internally validated (leave-one-out cross-validated coefficient of determination, [Formula: see text] = 0.714; leave-many-out coefficient of determination, [Formula: see text] = 0.738). External validation was carried out with the remaining half of the compounds (coefficient of determination for external validation, [Formula: see text] = 0.634). Two of the descriptors in the model (log P, average bonding information content) capture the structural characteristics describing penetration through bio-membranes. Another two descriptors (energy of highest occupied molecular orbital, weighted partial negative surface area) capture the electronic structural characteristics describing the interaction between the chemical and its hypothetic target in the cell. The applicability domain was subsequently analysed and discussed.

QSAR model for the prediction of bio-concentration factor using aqueous solubility and descriptors considering various electronic effects.

The in silico modelling of bio-concentration factor (BCF) is of considerable interest in environmental sciences, because it is an accepted indicator for the accumulation potential of chemicals in organisms. Numerous QSAR models have been developed for the BCF, and the majority utilize the octanol/water partition coefficient (log P) to account for the penetration characteristics of the chemicals. The present work used descriptors from a variety of software packages for the development of a multi-linear regression model to estimate BCF. The modelled data set of 473 diverse compounds covers a wide range of log BCF values. In the proposed QSAR model, most of the variation is described by the calculated solubility in water. Other contributing descriptors describe, for instance, hydrophobic surface area, hydrogen bonding and other electronic effects. The model was validated internally by using a variety of statistical approaches. Two external validations were also performed. For the former validation, a subset from the same data source was used. The 2nd external validation was based on an independent data set collected from different resources. All validations showed the consistency of the model. The applicability domain of the model was discussed and described and a thorough outlier analysis was performed.

Theoretical descriptors for the correlation of aquatic toxicity of environmental pollutants by quantitative structure-toxicity relationships.

Quantitative structure-toxicity relationships were developed for the prediction of aqueous toxicities for Poecilia reticulata (guppy) using the CODESSA treatment. A two-parameter correlation was found for class 1 toxins with R(2) = 0.96, and a five-parameter correlation was found for class 2 toxins with R(2) = 0.92. A five-parameter correlation for class 3 toxins had R(2) = 0.85. The correlations for class 4 toxins were less satisfactory. All the descriptors utilized are calculated solely from the structures of the molecules, which makes it possible to predict unavailable or unknown toxins.

Interpretation of quantitative structure-property and -activity relationships.

The potential utility of data reduction methods (e.g. principal component analysis) for the analysis of matrices assembled from the related properties of large sets of compounds is discussed by reference to results obtained from solvent polarity scales, ongoing work on solubilities and sweetness properties, and proposed general treatments of toxicities and gas chromatographic retention indices.

Correlation of the solubilities of gases and vapors in methanol and ethanol with their molecular structures.

Two four-parameter quantitative structure-property relations, with R2 = 0.95 and R2 = 0.97, respectively, gave good correlations for the solubilities of 87 gases and vapors in methanol and 61 in ethanol. All the descriptors used are derived solely from the structures of the molecules, making it possible to predict solubilities for unavailable or unknown compounds.

QSPR correlation and predictions of GC retention indexes for methyl-branched hydrocarbons produced by insects.

A successful interpretation of the complex manner by which the GC retention indexes of methylalkanes produced by insects are related to chemical structure was achieved using the quantitative structure-property relationship (QSPR) method. A general QSPR model including mainly topological descriptors was obtained for 178 data points. The error of the model is similar to the experimental error. The model was supported by (i) leave-one-out cross validation and (ii) division into three sets and prediction of each set from the other two. As a further test of the utility of the model, retention indexes were successfully predicted for an external set of 30 methyl-branched hydrocarbons not involved in the deduction of the correction equation from the main data set. General trends of the structural variation of compounds in any given range of retention index are discussed. The average error was 4.6 overall and 4.3 for the 165 compounds remaining after leaving out small monomethyl alkanes.

About the mutagenicity of chlorine-substituted furanones and halopropenals. A QSAR study using molecular orbital indices.

Electron affinities, frontier molecular orbital energies and electron densities at individual carbon atoms were calculated for 11 chlorofuranones including the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and for 5 halopropenals by semi-empirical AM1 and ab initio STO-3G methods. Significant correlations were found between Ames TA100 mutagenicity and the following AM1 electronic parameters of chlorofuranones: electron affinity (r = 0.9556). LUMO energy (r = 0.9332) and frontier electron density of LUMO at the alpha-carbon (r = 0.8882). In halopropenals only LUMO electron density at the beta-carbon correlates well with mutagenicity. The observed correlations suggest a reaction mechanism in which chlorofuranones and halopropenals act as electron acceptors in the interaction with DNA.