Atoxicophore is achemical structure or a portion of a structure (e.g., afunctional group) that is related to the toxic properties of a chemical. Toxicophores can act directly (e.g.,dioxins) or can requiremetabolic activation (e.g.,tobacco-specific nitrosamines).
Most toxic substances exert theirtoxicity through some interaction (e.g.,covalent bonding,oxidation) with cellularmacromolecules likeproteins orDNA. This interaction leads to changes in the normal cellularbiochemistry andphysiology and downstream toxic effects.Occasionally, the toxicophore requiresbioactivation, mediated byenzymes, to produce a more reactive metabolite that is more toxic. For example,tobacco-specific nitrosamines are activated bycytochrome P450 enzymes to form a more reactive substance that can covalently bind to DNA, causing mutations that, if notrepaired, can lead to cancer. Generally, different chemical compounds that contain the same toxicophore elicit similar toxic effects at the same site of toxicity.[1]
Medicinal chemists andstructural biologists study toxicophores in order to predict (and hopefully avoid) potentially toxic compounds early in the drug development process. Toxicophores can also be identified in lead compounds and removed or replaced later in the process with less toxicmoieties.[2] Both techniques,in silico (predictive) anda posteriori (experimental), are active areas ofchemoinformatics research and development, within the field known asComputational Toxicology.[3] For example, in the United States, theEPA's National Center for Computational Toxicology[4] sponsors several toxicity databases[5][6][7][8] based onpredictive modeling as well ashigh-throughput screening experimental methods.
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