A review of the electrophilic reaction chemistry involved in covalent protein binding relevant to toxicity

• Published in: Critical reviews in toxicology Vol. 41; no. 9; pp. 783 - 802
• Main Authors: Enoch, S. J., Ellison, C. M., Schultz, T. W., Cronin, M. T. D.
• Format: Journal Article
• Language: English
• Published: London Informa Healthcare 01.10.2011; Taylor & Francis
• Subjects: (Q)SAR Toolbox; Acylation; Biological and medical sciences; Chemical categories; covalent protein binding; electrophilic reaction chemistry; General aspects. Methods; Humans; Isocyanates - chemistry; Isocyanates - metabolism; Medical sciences; Nitrogen Compounds - chemistry; Nitrogen Compounds - metabolism; Protein Binding; Quantitative Structure-Activity Relationship; Quinones - chemistry; Quinones - metabolism; Risk Assessment; Software; structural alerts; Sulfur Compounds - chemistry; Sulfur Compounds - metabolism; Toxicity Tests; Toxicology; structural alerts; covalent protein binding; Toxicity; electrophilic reaction chemistry; Chemical compound; (Q)SAR Toolbox; Metabolism toxicity relation; Review; Electrophilic reaction; Binding protein; Structure activity relation; Covalent bond; In silico; Chemical categories; Bibliographic review
• ISSN: 1040-8444; 1547-6898
• DOI: 10.3109/10408444.2011.598141

Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories for the assessment of toxicological endpoints. For a number of endpoints, this requires a detailed knowledge of the electrophilic reaction chemistry that governs the ability of an exogenous chemical to form a covalent adduct. Historically, this chemistry has been defined as compilations of structural alerts without documenting the associated electrophilic chemistry mechanisms. To address this, this article has reviewed the literature defining the structural alerts associated with covalent protein binding and detailed the associated electrophilic reaction chemistry. This information is useful to both toxicologists and regulators when using the chemical category approach to fill data gaps for endpoints involving covalent protein binding. The structural alerts and associated electrophilic reaction chemistry outlined in this review have been incorporated into the OECD (Q)SAR Toolbox, a freely available software tool designed to fill data gaps in a regulatory environment without the need for further animal testing.