Validation of Toxtree and SciQSAR in silico predictive software using a publicly available benchmark mutagenicity database and their applicability for the qualification of impurities in pharmaceuticals.

The draft ICH M7 guidance (US FDA, 2013) recommends that the computational assessment of bacterial mutagenicity for the qualification of impurities in pharmaceuticals be performed using an expert rule-based method and a second statistically-based (Q)SAR method. The public nonproprietary 6489 compound Hansen benchmark mutagenicity data set was used as an external validation data set for Toxtree, a free expert rule-based SAR software. This is the largest known external validation of Toxtree. The Toxtree external validation specificity, sensitivity, concordance and false negative rate for this mutagenicity data set was 66%, 80%, 74% and 20%, respectively. This mutagenicity data set was also used to create a statistically-based SciQSAR-Hansen mutagenicity model. In a 10% leave-group-out internal cross validation study the specificity, sensitivity, concordance and false negative rate for the SciQSAR mutagenicity model was 71%, 83%, 77% and 17%, respectively. Combining Toxtree and SciQSAR predictions and scoring a positive finding in either software as a positive mutagenicity finding reduced the false negative rate to 7% and increased sensitivity to 93% at the expense of specificity which decreased to 53%. The results of this study support the applicability of Toxtree, and the SciQSAR-Hansen mutagenicity model for the qualification of impurities in pharmaceuticals.

Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities.

Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule-based expert system as their primary methodology, yielding negative predictivity values of ⩾78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review and/or a second QSAR methodology. Also in the latter case, an expert review was mandatory, especially when conflicting results were obtained. Based on the available data, we concluded that a rule-based expert system complemented by either expert knowledge or a second (Q)SAR model is appropriate. A maximal transparency of the assessment process (e.g. methods, results, arguments of weight-of-evidence approach) achieved by e.g. data sharing initiatives and the use of standards for reporting will enable regulators to fully understand the results of the analysis. Overall, the procedures presented here for structure-based assessment are considered appropriate for regulatory submissions in the scope of ICH M7.

Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities.

The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 µg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values.

Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans. Part A: use of FDA post-market reports to create a database of hepatobiliary and urinary tract toxicities.

The Informatics and Computational Safety Analysis Staff at the US FDA's Center for Drug Evaluation and Research has created a database of pharmaceutical adverse effects (AEs) linked to pharmaceutical chemical structures and estimated population exposures. The database is being used to develop quantitative structure-activity relationship (QSAR) models for the prediction of drug-induced liver and renal injury, as well as to identify relationships among AEs. The post-market observations contained in the database were obtained from FDA's Spontaneous Reporting System (SRS) and the Adverse Event Reporting System (AERS) accessed through Elsevier PharmaPendium software. The database contains approximately 3100 unique pharmaceutical compounds and 9685 AE endpoints. To account for variations in AE reports due to different patient populations and exposures for each drug, a proportional reporting ratio (PRR) was used. The PRR was applied to all AEs to identify chemicals that could be scored as positive in the training datasets of QSAR models. Additionally, toxicologically similar AEs were grouped into clusters based upon both biological effects and statistical correlation. This clustering created a weight of evidence paradigm for the identification of compounds most likely to cause human harm based upon findings in multiple related AE endpoints.

Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans: Part B. Use of (Q)SAR systems for early detection of drug-induced hepatobiliary and urinary tract toxicities.

This report describes the development of quantitative structure-activity relationship (QSAR) models for predicting rare drug-induced liver and urinary tract injury in humans based upon a database of post-marketing adverse effects (AEs) linked to approximately 1600 chemical structures. The models are based upon estimated population exposure using AE proportional reporting ratios. Models were constructed for 5 types of liver injury (liver enzyme disorders, cytotoxic injury, cholestasis and jaundice, bile duct disorders, gall bladder disorders) and 6 types of urinary tract injury (acute renal disorders, nephropathies, bladder disorders, kidney function tests, blood in urine, urolithiases). Identical training data sets were configured for 4 QSAR programs (MC4PC, MDL-QSAR, BioEpisteme, and Predictive Data Miner). Model performance was optimized and was shown to be affected by the AE scoring method and the ratio of the number of active to inactive drugs. The best QSAR models exhibited an overall average 92.4% coverage, 86.5% specificity and 39.3% sensitivity. The 4 QSAR programs were demonstrated to be complementary and enhanced performance was obtained by combining predictions from 2 programs (average 78.4% specificity, 56.2% sensitivity). Consensus predictions resulted in better performance as judged by both internal and external validation experiments.

Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans: Part C: use of QSAR and an expert system for the estimation of the mechanism of action of drug-induced hepatobiliary and urinary tract toxicities.

This report describes an in silico methodology to predict off-target pharmacologic activities and plausible mechanisms of action (MOAs) associated with serious and unexpected hepatobiliary and urinary tract adverse effects in human patients. The investigation used a database of 8,316,673 adverse event (AE) reports observed after drugs had been marketed and AEs noted in the published literature that were linked to 2124 chemical structures and 1851 approved clinical indications. The Integrity database of drug patent and literature studies was used to find pharmacologic targets and proposed clinical indications. BioEpisteme QSAR software was used to predict possible molecular targets of drug molecules and Derek for Windows expert system software to predict chemical structural alerts and plausible MOAs for the AEs. AEs were clustered into five types of liver injury: liver enzyme disorders, cytotoxic injury, cholestasis and jaundice, bile duct disorders, and gall bladder disorders, and six types of urinary tract injury: acute renal disorders, nephropathies, bladder disorders, kidney function tests, blood in urine, and urolithiasis. Results showed that drug-related AEs were highly correlated with: (1) known drug class warnings, (2) predicted off-target activities of the drugs, and (3) a specific subset of clinical indications for which the drug may or may not have been prescribed.

Combined Use of MC4PC, MDL-QSAR, BioEpisteme, Leadscope PDM, and Derek for Windows Software to Achieve High-Performance, High-Confidence, Mode of Action-Based Predictions of Chemical Carcinogenesis in Rodents.

ABSTRACT This report describes a coordinated use of four quantitative structure-activity relationship (QSAR) programs and an expert knowledge base system to predict the occurrence and the mode of action of chemical carcinogenesis in rodents. QSAR models were based upon a weight-of-evidence paradigm of carcinogenic activity that was linked to chemical structures (n = 1,572). Identical training data sets were configured for four QSAR programs (MC4PC, MDL-QSAR, BioEpisteme, and Leadscope PDM), and QSAR models were constructed for the male rat, female rat, composite rat, male mouse, female mouse, composite mouse, and rodent composite endpoints. Model predictions were adjusted to favor high specificity (>80%). Performance was shown to be affected by the method used to score carcinogenicity study findings and the ratio of the number of active to inactive chemicals in the QSAR training data set. Results demonstrated that the four QSAR programs were complementary, each detecting different profiles of carcinogens. Accepting any positive prediction from two programs showed better overall performance than either of the single programs alone; specificity, sensitivity, and Chi-square values were 72.9%, 65.9%, and 223, respectively, compared to 84.5%, 45.8%, and 151. Accepting only consensus-positive predictions using any two programs had the best overall performance and higher confidence; specificity, sensitivity, and Chi-square values were 85.3%, 57.5%, and 287, respectively. Specific examples are provided to demonstrate that consensus-positive predictions of carcinogenicity by two QSAR programs identified both genotoxic and nongenotoxic carcinogens and that they detected 98.7% of the carcinogens linked in this study to Derek for Windows defined modes of action.

In Silico Screening of Chemicals for Genetic Toxicity Using MDL-QSAR, Nonparametric Discriminant Analysis, E-State, Connectivity, and Molecular Property Descriptors.

ABSTRACT Genetic toxicity testing is a critical parameter in the safety assessment of pharmaceuticals, food constituents, and environmental and industrial chemicals. Quantitative structure-activity relationship (QSAR) software offers a rapid, cost-effective means of prioritizing the genotoxic potential of chemicals. Our goal is to develop and validate a complete battery of complementary QSAR models for genetic toxicity. We previously reported the development of MDL-QSAR models for the prediction of mutations in Salmonella typhimurium and Escherichia coli ( Contrera et al. 2005b ); this report describes the development of eight additional models for mutagenicity, clastogenicity, and DNA damage. The models were created using MDL-QSAR atom-type E-state, simple connectivity and molecular property descriptor categories, and nonparametric discriminant analysis. In 10% leave-group-out internal validation studies, the specificity of the models ranged from 63% for the mouse lymphoma (L5178Y-tk) model to 88% for chromosome aberrations in vivo. Sensitivity ranged from a high of 74% for the mouse lymphoma model to a low of 39% for the unscheduled DNA synthesis model. The receiver operator characteristic (ROC) was >/=2.00, a value indicative of good predictive performance. The predictive performance of MDL-QSAR models was also shown to compare favorably to the results of MultiCase MC4PC ( Matthews et al. 2006b ) genotoxicity models prepared with the same training data sets. MDL-QSAR software models exhibit good specificity, sensitivity, and coverage and they can provide rapid and cost-effective large-scale screening of compounds for genotoxic potential by the chemical and pharmaceutical industry and for regulatory decision support applications.

Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.

ABSTRACT Drug-induced phospholipidosis (PL) is a condition characterized by the accumulation of phospholipids and drug in lysosomes, and is found in a variety of tissue types. PL is frequently manifested in preclinical studies and may delay or prevent the development of pharmaceuticals. This report describes the construction of a database of PL findings in a variety of animal species and its use as a training data set for computational toxicology software. PL data and chemical structures were compiled from the published literature, existing pharmaceutical databases, and Food and Drug Administration (FDA) internal reports yielding a total of 583 compounds suitable for modeling. The database contained 190 (33%) positive drugs and 393 (77%) negative drugs, of which 39 were electron microscopy-confirmed negative compounds and 354 were classified as negatives due to the absence of positive reported data. Of the 190 positive findings, 76 were electron microscopy confirmed and 114 were considered positive based on other evidence. Quantitative structure-activity relationship (QSAR) models were constructed using two commercially available software programs, MC4PC and MDL-QSAR, and internal cross-validation (10 x 10%) experiments were performed to assess their predictive performance. Performance parameters for the MC4PC model were specificity 92%, sensitivity 50%, concordance 78%, positive predictivity 76%, and negative predictivity 78%. For MDL-QSAR, predictive performance was similar: specificity 80%, sensitivity 76%, concordance 79%, positive predictivity 65%, and negative predictivity 87%. By combining the output of the two QSAR programs, the overall predictive performance was vastly improved and sensitivity could be optimized to 81% without significant loss of specificity (79%). Many of the structural alerts and significant molecular descriptors obtained from the QSAR software were found to be associated with parts of active molecules known for their cationic amphiphilic drug (CAD) properties supporting the hypothesis that the endpoint of PL is statistically correlated with chemical structure. QSAR models can be useful tools for screening drug candidate molecules for potential PL.

Comparison of MC4PC and MDL-QSAR rodent carcinogenicity predictions and the enhancement of predictive performance by combining QSAR models.

This report presents a comparison of the predictive performance of MC4PC and MDL-QSAR software as well as a method for combining the predictions from both programs to increase overall accuracy. The conclusions are based on 10 x 10% leave-many-out internal cross-validation studies using 1540 training set compounds with 2-year rodent carcinogenicity findings. The models were generated using the same weight of evidence scoring method previously developed [Matthews, E.J., Contrera, J.F., 1998. A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. Regul. Toxicol. Pharmacol. 28, 242-264.]. Although MC4PC and MDL-QSAR use different algorithms, their overall predictive performance was remarkably similar. Respectively, the sensitivity of MC4PC and MDL-QSAR was 61 and 63%, specificity was 71 and 75%, and concordance was 66 and 69%. Coverage for both programs was over 95% and receiver operator characteristic (ROC) intercept statistic values were above 2.00. The software programs had complimentary coverage with none of the 1540 compounds being uncovered by both MC4PC and MDL-QSAR. Merging MC4PC and MDL-QSAR predictions improved the overall predictive performance. Consensus sensitivity increased to 67%, specificity to 84%, concordance to 76%, and ROC to 4.31. Consensus rules can be tuned to reflect the priorities of the user, so that greater emphasis may be placed on predictions with high sensitivity/low false negative rates or high specificity/low false positive rates. Sensitivity was optimized to 75% by reclassifying all compounds predicted to be positive in MC4PC or MDL-QSAR as positive, and specificity was optimized to 89% by reclassifying all compounds predicted negative in MC4PC or MDL-QSAR as negative.

Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling.

Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest is MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals, comprised primarily of pharmaceutical, industrial and some natural products developed under an FDA-MDL cooperative research and development agreement (CRADA). The predictive performance for this group of dietary natural products and the control group was 97% sensitivity and 80% concordance. Specificity was marginal at 53%. This study finds that the in silico QSAR analysis employing this software's rodent carcinogenicity database is capable of identifying the rodent carcinogenic potential of naturally occurring organic molecules found in the human diet with a high degree of sensitivity. It is the first study to demonstrate successful QSAR predictive modeling of naturally occurring carcinogens found in the human diet using an external validation test. Further test validation of this software and expansion of the training data set for dietary chemicals will help to support the future use of such QSAR methods for screening and prioritizing the risk of dietary chemicals when actual animal data are inadequate, equivocal, or absent.

In silico approaches to explore toxicity end points: issues and concerns for estimating human health effects.

The European Chemicals Bureau and the Organisation for Economic Cooperation and Development are currently compiling a sanctioned list of quantitative structure-activity relationship (QSAR) risk assessment models and data sets to predict the physiological properties, environmental fate, ecological effects and human health effects of new and existing chemicals in commerce in the European Union. This action implements the technical requirements of the European Commission's Registration, Evaluation and Authorisation of Chemicals legislation. The goal is to identify a battery of QSARs that can furnish rapid, reliable and cost-effective decision support information for regulatory decisions that can substitute for results from animal studies. This report discusses issues and concerns that need to be addressed when selecting QSARs to predict human health effect end points.

Progress in QSAR toxicity screening of pharmaceutical impurities and other FDA regulated products.

Active ingredients in pharmaceutical products undergo extensive testing to ensure their safety before being made available to the American public. A consideration during the regulatory review process is the safety of pharmaceutical contaminants and degradents which may be present in the drug product at low levels. Several published guidances are available that outline the criteria for further testing of these impurities to assess their toxic potential, where further testing is in the form of a battery of toxicology assays and the identification of known structural alerts. However, recent advances in the development of computational methods have made available additional resources for safety assessment such as structure similarity searching and quantitative structure-activity relationship (QSAR) models. These methods offer a rapid and cost-effective first-pass screening capability to assess toxicity when conventional toxicology data are limited or lacking, with the potential to identify compounds that would be appropriate for further testing. This article discusses some of the considerations when using computational toxicology methods for regulatory decision support and gives examples of how the technology is currently being applied at the US Food and Drug Administration.

A comprehensive model for reproductive and developmental toxicity hazard identification: I. Development of a weight of evidence QSAR database.

A weight of evidence (WOE) reproductive and developmental toxicology (reprotox) database was constructed that is suitable for quantitative structure-activity relationship (QSAR) modeling and human hazard identification of untested chemicals. The database was derived from multiple publicly available reprotox databases and consists of more than 10,000 individual rat, mouse, or rabbit reprotox tests linked to 2134 different organic chemical structures. The reprotox data were classified into seven general classes (male reproductive toxicity, female reproductive toxicity, fetal dysmorphogenesis, functional toxicity, mortality, growth, and newborn behavioral toxicity), and 90 specific categories as defined in the source reprotox databases. Each specific category contained over 500 chemicals, but the percentage of active chemicals was low, generally only 0.1-10%. The mathematical WOE model placed greater significance on confirmatory observations from repeat experiments, chemicals with multiple findings within a category, and the categorical relatedness of the findings. Using the weighted activity scores, statistical analyses were performed for specific data sets to identify clusters of categories that were correlated, containing similar profiles of active and inactive chemicals. The analysis revealed clusters of specific categories that contained chemicals that were active in two or more mammalian species (trans-species). Such chemicals are considered to have the highest potential risk to humans. In contrast, some specific categories exhibited only single species-specific activities. Results also showed that the rat and mouse were more susceptible to dysmorphogenesis than rabbits (6.1- and 3.6-fold, respectively).

Genetic toxicity assessment: employing the best science for human safety evaluation. Part I: Early screening for potential human mutagens.

Results of genetic toxicology tests are used by FDA's Center for Drug Evaluation and Research as a surrogate for carcinogenicity data during the drug development process. Mammalian in vitro assays have a high frequency of positive results which can impede or derail the drug development process. To reduce the risk of such delays, most pharmaceutical companies conduct early non-GLP (good laboratory practices) studies to eliminate drug candidate with mutagenic or clastogenic activity. Early screens include in silico structure activity assessments and various iterations of the ultimate regulatory mandated GLP studies.

A comprehensive model for reproductive and developmental toxicity hazard identification: II. Construction of QSAR models to predict activities of untested chemicals.

This report describes the construction, optimization and validation of a battery of quantitative structure-activity relationship (QSAR) models to predict reproductive and developmental (reprotox) hazards of untested chemicals. These models run with MC4PC software to predict seven general reprotox classes: male and female reproductive toxicity, fetal dysmorphogenesis, functional toxicity, mortality, growth, and newborn behavioral toxicity. The reprotox QSARs incorporate a weight of evidence paradigm using rats, mice, and rabbit reprotox study data and are designed to identify trans-species reprotoxicants. The majority of the reprotox QSARs exhibit good predictive performance properties: high specificity (>80%), low false positives (<20%), significant receiver operating characteristic (ROC) values (>2.00), and high coverage (>80%) in 10% leave-many-out validation experiments. The QSARs are based on 627-2023 chemicals and exhibited a wide applicability domain for FDA regulated organic chemicals for which they were designed. Experiments were also performed using the MC4PC multiple module prediction technology, and ROC statistics, and adjustments to the ratio of active to inactive (A/I ratio) chemicals in training data sets were made to optimize the predictive performance of QSAR models. Results revealed that an A/I ratio of approximately 40% was optimal for MC4PC. We discuss specific recommendations for the application of the reprotox QSAR battery.

An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints.

A retrospective analysis of standard genetic toxicity (genetox) tests, reproductive and developmental toxicity (reprotox) studies, and rodent carcinogenicity bioassays (rcbioassay) was performed to identify the genetox and reprotox endpoints whose results best correlate with rcbioassay observations. A database of 7205 chemicals with genetox (n = 4961), reprotox (n = 2173), and rcbioassay (n = 1442) toxicity data was constructed; 1112 of the chemicals have both genetox and rcbioassay data and 721 chemicals have both reprotox and rcbioassay data. This study differed from previous studies by using conservative weight of evidence criteria to classify chemical carcinogens, data from 63 genetox and reprotox toxicological endpoints, and a new statistical parameter of correlation indicator (CI, the average of specificity and positive predictivity) to identify good surrogate endpoints for predicting carcinogenicity. Among 63 endpoints, results revealed that carcinogenicity was well correlated with certain tests for gene mutation (n = 8), in vivo clastogenicity (n = 2), unscheduled DNA synthesis assay (n = 1), and reprotox (n = 3). The current FDA regulatory battery of four genetox tests used to predict carcinogenicity includes two tests with good correlation (gene mutation in Salmonella and in vivo micronucleus) and two tests with poor correlation (mouse lymphoma gene mutation and in vitro chromosome aberrations) by our criteria.

An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: II. Identification of genotoxicants, reprotoxicants, and carcinogens using in silico methods.

This study examined a novel method to identify carcinogens that employed expanded data sets composed of in silico data pooled with actual experimental genetic toxicity (genetox) and reproductive and developmental toxicity (reprotox) data. We constructed 21 modules using the MC4PC program including 13 of 14 (11 genetox and 3 reprotox) tests that we found correlated with results of rodent carcinogenicity bioassays (rcbioassays) [Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., Contrera, J.F., 2005b. An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints. Regul. Toxicol. Pharmacol.]. Each of the 21 modules was evaluated by cross-validation experiments and those with high specificity (SP) and positive predictivity (PPV) were used to predict activities of the 1442 chemicals tested for carcinogenicity for which actual genetox or reprotox data were missing. The expanded data sets had approximately 70% in silico data pooled with approximately 30% experimental data. Based upon SP and PPV, the expanded data sets showed good correlation with carcinogenicity testing results and had correlation indicator (CI, the average of SP and PPV) values of 75.5-88.7%. Conversely, expanded data sets for 9 non-correlated test endpoints were shown not to correlate with carcinogenicity results (CI values <75%). Results also showed that when Salmonella mutagenic carcinogens were removed from the 12 correlated, expanded data sets, only 7 endpoints showed added value by detecting significantly more additional carcinogens than non-carcinogens.

In silico screening of chemicals for bacterial mutagenicity using electrotopological E-state indices and MDL QSAR software.

Quantitative structure-activity relationship (QSAR) software offers a rapid, cost effective means of prioritizing the mutagenic potential of chemicals. MDL QSAR models were developed using atom-type E-state indices and non-parametric discriminant analysis. Models were developed for Salmonella typhimurium gene mutation, combining results from strains TA97, TA98, TA100, TA1535, TA1536, TA1537, and TA1538 (n=3228), and Escherichia coli gene mutation tests WP2, WP100, and polA (n=472). Composite microbial mutation models (n=3338) were developed combining all Salmonella, E. coli, and the Bacillus subtilis rec spot test study results. The datasets contained 74% non-pharmaceuticals and 26% pharmaceuticals. Salmonella and microbial mutagenesis external validation studies included a total of 1444 and 1485 compounds, respectively. The average specificity, sensitivity, positive predictivity, concordance, and coverage of Salmonella models was 76, 81, 73, 78, and 98%, respectively, with similar performance for the microbial mutagenesis models. MDL QSAR and discriminant analysis provides rapid and highly automated mutagenicity screening software with good specificity, sensitivity, and coverage that is simpler and requires less user intervention than other similar software. MDL QSAR modules for microbial mutagenicity can provide efficient and cost effective large scale screening of compounds for mutagenic potential for the chemical and pharmaceutical industry.