The Identification of Toxicophores for the Prediction of Mutagenicity, Hepatotoxicity and Cardiotoxicity

The toxic properties of compounds can be related to chemical structures, and more specifically, to particular substructures,called toxicophores. Reliability and accuracy of mutagenicity, hepatotoxicity, or cardiotoxicity predictions may be achieved by identifying toxicophores. These predictions can guide the design of chemical libraries for hit and lead optimization. As such, a thorough molecular knowledge in drug-induced toxicity is required to aid the development of new therapeutic agents and prevent the release of potentially toxic drugs onto the market. The incorporation of these potentially reactive chemical moieties within new therapeutic agents should be limited. This, however, can not always be prevented, particularly when the structural feature responsible for toxicity is also responsible for the pharmacological efficacy.In recent years, there has been strong pressure from society in general, and from government agencies in particular, to develop “general” prediction models in order to cope with the thousands of chemicals present in the environment for which experimental data are not available and likely will never exist. Therefore, one of the objectives of this work is to introduce methodologies capable of identifying the potential environmental health hazards of chemicals. This review also summarizes the evidence for reactive metabolite formation from chemical carcinogens, hepatotoxic drugs, and also describes how and where molecules bind and inhibit hERG K+ channels, causing cardiotoxicity by QT prolongation. Such information should dramatically improve our understanding of drug-induced toxic reactions. Indeed, pharmaceutical companies are striving to improve the drug discovery and development process to identify, as early as possible, the risk of novel agents, or their metabolites, causing mutagenicity, hepatocellular toxicity, or QT interval prolongation and to make appropriate go/no-go decisions or modify their development programs accordingly.