Identification Of Structural Alerts Research Articles

Exploration of structural requirements for azole chemicals towards human aromatase CYP19A1 activity: Classification modeling, structure-activity relationships and read-across study

Human aromatase, also called CYP19A1, plays a major role in the conversion of androgens into estrogens. Inhibition of aromatase is an important target for estrogen receptor (ER)-responsive breast cancer therapy. Use of azole compounds as aromatase inhibitors is widespread despite their low selectivity. A toxicological evaluation of commonly used azole-based drugs and agrochemicals with respect to CYP19A1 is currently requested by the European Union- Registration, Evaluation, Authorization and Restriction of Chemicals (EU-REACH) regulations due to their potential as endocrine disruptors. In this connection, identification of structural alerts (SAs) is an effective strategy for the toxicological assessment and safe drug design. The present study describes the identification of SAs of azole-based chemicals as guiding experts to predict the aromatase activity. Total 21 SAs associated with aromatase activity were extracted from dataset of 326 azole-based drugs/chemicals obtained from Tox21 library. A cross-validated classification model having high accuracy (error rate 5%) was proposed which can precisely classify azole chemicals into active/inactive toward aromatase. In addition, mechanistic details and toxicological properties (agonism/antagonism) of azoles with respect to aromatase were explored by comparing active and inactive chemicals using structure-activity relationships (SAR). Lastly, few structural alerts were applied to form chemical categories for read-across applications.

Fragment Prioritization on a Large Mutagenicity Dataset.

The identification of structural alerts is one of the simplest tools used for the identification of potentially toxic chemical compounds. Structural alerts have served as an aid to quickly identify chemicals that should be either prioritized for testing or for elimination from further consideration and use. In the recent years, the availability of larger datasets, often growing in the context of collaborative efforts and competitions, created the raw material needed to identify new and more accurate structural alerts. This work applied a method to efficiently mine large toxicological dataset for structural alert showing a strong statistical association with mutagenicity. In details, we processed a large Ames mutagenicity dataset comprising 14,015 unique molecules obtained by joining different data sources. After correction for multiple testing, we were able to assign a probability value to each fragment. A total of 51 rules were identified, with p-value < 0.05. Using the same method, we also confirmed the statistical significance of several mutagenicity rules already present and largely recognized in the literature. In addition, we have extended the application of our method by predicting the mutagenicity of an external data set.

Quantitative structure-activity relationship modelling of the carcinogenic risk of nitroso compounds using regression analysis and the TOPS-MODE approach

Worldwide, legislative and governmental efforts are focusing on establishing simple screening tools for identifying those chemicals most likely to cause adverse effects without experimentally testing all chemicals of regulatory concern. This is because even the most basic biological testing of compounds of concern, apart from requiring a huge number of test animals, would be neither resource nor time effective. Thus, alternative approaches such as the one proposed here, quantitative structure-activity relationship (QSAR) modelling, are increasingly being used for identifying the potential health hazards and subsequent regulation of new industrial chemicals. This paper follows up on our earlier work that demonstrated the use of the TOPological Substructural MOlecular DEsign (TOPS-MODE) approach to QSAR modelling for predictions of the carcinogenic potency of nitroso compounds. The data set comprises 56 nitroso compounds which have been bio-assayed in female rats and administered by the oral water route. The QSAR model was able to account for about 81% of the variance in the experimental activity and exhibited good cross-validation statistics. A reasonable interpretation of the TOPS-MODE descriptors was achieved by means of bond contributions, which in turn afforded the recognition of structural alerts (SAs) regarding carcinogenicity. A comparison of the SAs obtained from different data sets showed that experimental factors, such as the sex and the oral administration route, exert a major influence on the carcinogenicity of nitroso compounds. The present and previous QSAR models combined together provide a reliable tool for estimating the carcinogenic potency of yet untested nitroso compounds and they should allow the identification of SAs, which can be used as the basis of prediction systems for the rodent carcinogenicity of these compounds.

Quantitative structure carcinogenicity relationship for detecting structural alerts in nitroso-compounds: Species: Rat; Sex: Male; Route of administration: Water

In this work, Quantitative Structure−Activity Relationship (QSAR) modelling was used as a tool for predicting the carcinogenic potency of a set of 39 nitroso-compounds, which have been bioassayed in male rats by using the oral route of administration. The optimum QSAR model provided evidence of good fit and performance of predicitivity from training set. It was able to account for about 84% of the variance in the experimental activity and exhibited high values of the determination coefficients of cross validations, leave one out and bootstrapping ( q 2 LOO = 78.53 and q 2 Boot = 74.97). Such a model was based on spectral moments weighted with Gasteiger–Marsilli atomic charges, polarizability and hydrophobicity, as well as with Abraham indexes, specifically the summation solute hydrogen bond basicity and the combined dipolarity/polarizability. This is the first study to have explored the possibility of combining Abraham solute descriptors with spectral moments. A reasonable interpretation of these molecular descriptors from a toxicological point of view was achieved by means of taking into account bond contributions. The set of relationships so derived revealed the importance of the length of the alkyl chains for determining carcinogenic potential of the chemicals analysed, and were able to explain the difference between mono-substituted and di-substituted nitrosoureas as well as to discriminate between isomeric structures with hydroxyl-alkyl and alkyl substituents in different positions. Moreover, they allowed the recognition of structural alerts in classical structures of two potent nitrosamines, consistent with their biotransformation. These results indicate that this new approach has the potential for improving carcinogenicity predictions based on the identification of structural alerts.

Optimal dose identification: predicting a safe dose in man from animal studies

Adverse drug reactions remain a major clinical problem and impairment to safe drug development. The CPMP provides guidelines for preclinical studies. Safety margins for target-organ toxicity must be calculated. It is necessary to be aware of species differences in pharmacodynamic effects and in routes and rates of metabolism. The relevance of the test system to the intended human use must be defined. It is important to learn lessons from past experience with drugs that have caused serious toxicity in man. Idiosyncratic toxicity is only detected late in drug development. The pathophysiology of such reactions is complex and poorly understood. In man, genetics and disease may be predisposing factors. Therefore, it is not surprising that conventional animal models fail to identify drugs which cause idiosyncratic toxicity. At present, we have to depend on the identification of structural alerts in drugs and metabolites to screen out the potential for toxicity. Recent advances in molecular toxicology allow the investigator to explore biochemical stress, in both in vitro and in vivo models, at doses of drugs and chemicals that do not cause overt toxicity. It is, thus, possible to address physiological, pharmacological and toxicological aspects of adverse reactions. Ultimately, it may be possible to relate cellular changes in these test systems to serious toxicities seen in man (anaphylaxis, hepatotoxicity, blood dyscrasias and severe skin reactions) and, thus, provide more physiologically relevant assays for the prediction of human drug toxicity.