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  ...Introduction to Ames mutagenicity

CSGenoTox  Predictor Capabilities

CSGenoTox Calculates the Following Prediction:

Mutagenic Index (MI) binary value of 1 (mutagen/positive) or 0 (non-mutagen/negative)

The only input required from the user is a structure for each compound to be predicted.  The structure may be submitted as either a MOL file or SD file and it is not necessary for the structure to be in a three dimensional format or to be optimized to a minimum energy confirmation.

Genotoxicity and Mutagenicity

Genotoxicity is defined as, "An organism-specific and quantitative measure of the potential of a specific chemical or electromagnetic environment to cause damage to the DNA of a cell." (1)

The Mutagenic Index (MI) is binary value of 1 or 0 that is assigned to a compound, where 1 indicates a mutagen (positive) and 0 indicates a non-mutagen (negative).

Mutagenicity is an effect that occurs when cellular DNA is altered as a result of its interaction with a chemical entity. DNA may be altered by interaction with a drug in several ways, such as the formation of a covalent bond between the drug and the DNA.  The result of the formation of such a covalent bond is a specific adduct or physical alteration of DNA which may lead to such complications as nucleotide strand breakage or the disruption of replication or translation.  The three principal classes of drug interaction with DNA are intercalators, alkylators, and DNA strand breakers.  Most of these effects are the result of irreversible binding of the drug to that DNA and all three modes of interaction have mutagenic consequences. .

Genotoxic chemicals are generally electrophilic in nature either directly through microsomal activation (S9), which results in the ability of the chemical to react with DNA through alkylation.  Further, genotoxic changes can also occur indirectly with non-electrophilic entities, which interfere with molecules or enzymes associated with DNA synthesis or chromosomal segregation.  Therefore, genotoxic compounds may act directly or indirectly with DNA to produce non-lethal, but harmful heritable changes in the structure or arrangement of genes.

(1) P. Corbisier and D. Barcelo, Conclusions: "Proceedings of the BIOSET Technical Workshop on Genotoxicity Biosensing"

Results from genotoxicity testing may be the only early warning of the potential for long term toxic effects of a pharmaceutical compound.  Many diseases exhibit late onset with the initial insult occurring many years before.  For this reason, genotoxicity tests are the only current in vitro assays that are part of regulatory packages.  Ames testing is one such test.  Reverse mutation assay in Salmonella typhiumurium, a histidine-requiring autotroph, is one of the most commonly used assays, commonly called the Ames genotoxicity test.  A compound is deemed genotoxic if the count of prototrophic reverant colonies are at least 3-fold the number found in the controls (non-mutants). For negative results, the mean plate counts must be less the 1.5-fold those of the controls. Therefore, the outcome of Ames test can be considered binary; 0 for negative and 1 for positive results.

There are several different test strains (e.g., TA100,TA98, TA102, TA104) used with Ames test with or without S9 activation.  TA100 and TA98 have the broadest specificity and are used in early drug testing.  CSGenoTox predicts a mutagenic Index (MI) for compounds giving either a 0 or 1 as output to indict the predicted absence or presence of genotoxicity for new chemical entities being screened.  The first release of CSGenoTox was built with data from 3363 compounds (see Dataset Profile).

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