کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2568824 1128486 2013 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
In silico modeling to predict drug-induced phospholipidosis
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
In silico modeling to predict drug-induced phospholipidosis
چکیده انگلیسی


• New in silico models for predicting drug-induced phospholipidosis (DIPL) are described.
• The training set data in the models is derived from the FDA's phospholipidosis database.
• We find excellent predictivity values of the models based on external validation.
• The models can support drug screening and regulatory decision-making on DIPL.

Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 269, Issue 2, 1 June 2013, Pages 195–204
نویسندگان
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