title: Hybrid optimal descriptors as a tool to predict skin sensitization in accordance to OECD principles.
abstract: Skin sensitization (allergic contact dermatitis) is a widespread problem arising from the contact of chemicals with the skin. The detection of molecular features with undesired effect for skin is complex task owing to unclear biochemical mechanisms and unclearness of conditions of action of chemicals to skin. The development of computational methods for estimation of this endpoint in order to reduce animal testing is recommended (Cosmetics Directive EC regulation 1907/2006; EU Regulation, Regulation, 1223/2009). The CORAL software (http://www.insilico.eu/coral) gives good predictive models for the skin sensitization. Simplified molecular input-line entry system (SMILES) together with molecular graph are used to represent the molecular structure for these models. So-called hybrid optimal descriptors are used to establish quantitative structure-activity relationships (QSARs). The aim of this study is the estimation of the predictive potential of the hybrid descriptors. Three different distributions into the training (≈70%), calibration (≈15%), and validation (≈15%) sets are studied. QSAR for these three distributions are built up with using the Monte Carlo technique. The statistical characteristics of these models for external validation set are used as a measure of predictive potential of these models. The best model, according to the above criterion, is characterized by nvalidation=29, r2validation=0.8596, RMSEvalidation=0.489. Mechanistic interpretation and domain of applicability for these models are defined.
authors.affiliation: IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156, Via La Masa 19, Milano, Italy. Electronic address: alla.toropova@marionegri.it.
authors.forename: Alla P
authors.initials: AP
authors.lastname: Toropova
authors.affiliation: IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156, Via La Masa 19, Milano, Italy.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Toropov
mesh_terms: D000826:Animal Testing Alternatives / Q000592:standards; D017449:Dermatitis, Allergic Contact / Q000209:etiology; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D009930:Organic Chemicals / Q000737:chemistry / Q000633:toxicity; D066150:Organisation for Economic Co-Operation and Development; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D012984:Software
chemical_list: D009930:Organic Chemicals
keywords: CORAL software; Monte Carlo method; OECD principles; QSAR; SMILES; Skin sensitization