Determination of Toxicant Mode of Action by Augmented Top Priority Fragment Class

Abstract

Theoretical models can be an efficient tool to assess compound toxicity as an alternative to experimental determinations. Their application must follow some requirements that include the possibility of understanding the rationale that supports the prediction; here, the determination of the mode of action (MOA) is important. A combination of similarity and reactivity analysis has been applied to group chemical compounds with the aim at selecting groups that share structure and electronic state. The model is not based on experimental data but only on structural features. The result is a number of groups that contains similar compounds with similar reactivity and, possibly, similar MOA. The comparison of these groups to the experimentally determined MOAs available for the EPAFHAM database permits the discussion of the validity of both the model and the experimental data.

A chemo-centric view of human health and disease

“…In this regard, reactivity prediction methods should be appropriate 33 , particularly for nonspecific complications like tissue necrosis, carcinogenicity, or immune-mediated toxicities. Recently, a combination of structure and reactivity analysis was applied to select groups that shared structure and electronic state 34 , and it was recommended that compounds undergo a structural clustering before the reactivity assessment, suggesting that our results could be readily complemented with reactivity profiles.…”

A History of the Molecular Initiating Event

“…Biosystem disturbance has been alluded to in several cases 37,49 and provides an MIE category for the narcosis mode of action often used in ecotoxicology which is associated with membrane disruption. 34 Other biosystem disturbance MIEs include chemicals which act as protonophores or redox cyclers leading to mitochondrial toxicity endpoints. 65 The impact of the MIE and AOP framework has undoubtedly increased over the past 3 years, with the number of publications contributing to the area increasing each year.…”

“…A final category of MIEs is for those chemicals that do not directly interact with a specific biomolecule, but rather cause a disturbance in cellular or organelle biosystems. Biosystem disturbance has been alluded to in several cases , and provides an MIE category for the narcosis mode of action often used in ecotoxicology which is associated with membrane disruption . Other biosystem disturbance MIEs include chemicals which act as protonophores or redox cyclers leading to mitochondrial toxicity endpoints …”

“…Casalegno and Sello published a similar study predicting mode of action of environmental toxicants by structural similarity. 34 These models were based not on experimental data, but on structural features alone. This approach relies on the fact that the interaction between well-characterized molecules and an ill-defined biological target depends on the chemistry of both parts.…”

“…Casalegno and Sello published a similar study predicting mode of action of environmental toxicants by structural similarity . These models were based not on experimental data, but on structural features alone.…”