title: CADRE-SS, an in Silico Tool for Predicting Skin Sensitization Potential Based on Modeling of Molecular Interactions.
abstract: Using computer models to accurately predict toxicity outcomes is considered to be a major challenge. However, state-of-the-art computational chemistry techniques can now be incorporated in predictive models, supported by advances in mechanistic toxicology and the exponential growth of computing resources witnessed over the past decade. The CADRE (Computer-Aided Discovery and REdesign) platform relies on quantum-mechanical modeling of molecular interactions that represent key biochemical triggers in toxicity pathways. Here, we present an external validation exercise for CADRE-SS, a variant developed to predict the skin sensitization potential of commercial chemicals. CADRE-SS is a hybrid model that evaluates skin permeability using Monte Carlo simulations, assigns reactive centers in a molecule and possible biotransformations via expert rules, and determines reactivity with skin proteins via quantum-mechanical modeling. The results were promising with an overall very good concordance of 93% between experimental and predicted values. Comparison to performance metrics yielded by other tools available for this endpoint suggests that CADRE-SS offers distinct advantages for first-round screenings of chemicals and could be used as an in silico alternative to animal tests where permissible by legislative programs.
authors.affiliation: Computational Biology Institute, The George Washington University , 45085 University Drive Suite 305, Ashburn, Virginia 20147, United States.|DOT Consulting LLC , 113 South Columbus Street Suite 100, Alexandria, Virginia 22314, United States.
authors.forename: Jakub
authors.initials: J
authors.lastname: Kostal
authors.affiliation: Department of Chemistry, The George Washington University , 800 22nd Street Northwest, Washington, D.C. 20052, United States.
authors.forename: Adelina
authors.initials: A
authors.lastname: Voutchkova-Kostal
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D009010:Monte Carlo Method; D009930:Organic Chemicals / Q000737:chemistry* / Q000633:toxicity*; D010539:Permeability / Q000187:drug effects; D012867:Skin / Q000187:drug effects*; D012869:Skin Absorption / Q000187:drug effects; D023422:Skin Irritancy Tests / Q000379:methods*
chemical_list: D009930:Organic Chemicals