کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
11031879 1645770 2018 48 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Construction and application of (Q)SAR models to predict chemical-induced in vitro chromosome aberrations
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Construction and application of (Q)SAR models to predict chemical-induced in vitro chromosome aberrations
چکیده انگلیسی
In drug development, genetic toxicology studies are conducted using in vitro and in vivo assays to identify potential mutagenic and clastogenic effects, as outlined in the International Council for Harmonisation (ICH) S2 regulatory guideline. (Quantitative) structure-activity relationship ((Q)SAR) models that predict assay outcomes can be used as an early screen to prioritize pharmaceutical candidates, or later during product development to evaluate safety when experimental data are unavailable or inconclusive. In the current study, two commercial QSAR platforms were used to build models for in vitro chromosomal aberrations in Chinese hamster lung (CHL) and Chinese hamster ovary (CHO) cells. Cross-validated CHL model predictive performance showed sensitivity of 80 and 82%, and negative predictivity of 75 and 76% based on 875 training set compounds. For CHO, sensitivity of 61 and 67% and negative predictivity of 68 and 74% was achieved based on 817 training set compounds. The predictive performance of structural alerts in a commercial expert rule-based SAR software was also investigated and showed positive predictivity of 48-100% for selected alerts. Case studies examining incorrectly-predicted compounds, non-DNA-reactive clastogens, and recently-approved pharmaceuticals are presented, exploring how an investigational approach using similarity searching and expert knowledge can improve upon individual (Q)SAR predictions of the clastogenicity of drugs.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Regulatory Toxicology and Pharmacology - Volume 99, November 2018, Pages 274-288
نویسندگان
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