Mode-of-Action-Guided, Molecular Modeling-Based Toxicity Prediction: A Novel Approach for In Silico Predictive Toxicology

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Computing Sciences and Computer Engineering


Computational toxicology is a sub-discipline of toxicology concerned with the development and use of computer-based models and methodology to understand and predict chemical toxicity in a biological system (e.g., cells and organisms). Quantitative structure–activity relationship (QSAR) has been the predominant approach in computational toxicology. However, classical QSAR methodology has often suffered from low prediction accuracy, largely owing to the lack or non-integration of toxicological mechanisms. To address this lingering problem, we have developed a novel in silico toxicology approach that is based on molecular modeling and guided by mode of action (MoA). Our approach is implemented through a target-specific toxicity knowledgebase (TsTKb), consisting of a pre-categorized database of chemical MoA (ChemMoA) and a series of pre-built, category-specific classification and quantification models. ChemMoA serves as the depository of chemicals with known MoAs or molecular initiating events (i.e., known target biomacromolecules) and quantitative information for measured toxicity endpoints (if available). The models allow a user to qualitatively classify an uncharacterized chemical by MoA and quantitatively predict its toxicity potency. This approach is currently under development and will evolve to incorporate physiologically based pharmacokinetic (PBPK) modeling to address absorption, distribution, metabolism and excretion (ADME) processes in a biological system. The fully developed approach is believed to significantly advance in silico -based predictive toxicology and provide a new powerful toolbox for regulators, the chemical industry and the relevant academic communities.

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Challenges and Advances in Computational Chemistry and Physics



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