Clearance Mechanism Assignment and Total Clearance Prediction in Human Based upon in Silico Models

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• 作者：Franco Lombardo ; R. Scott Obach ; Manthena V. Varma ; Rowan Stringer ; Giuliano Berellini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4397-4405
• 全文大小：345K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

We introduce a two-tier model based on an exhaustive data set, where discriminant models based on principal component analysis (PCA) and partial least squares (PLS) are used separately and in conjunction, and we show that PCA is highly discriminant approaching 95% accuracy in the assignment of the primary clearance mechanism. Furthermore, the PLS model achieved a quantitative predictive performance comparable to methods based on scaling of animal data while not requiring the use of either in vivo or in vitro data, thus sparing the use of animal. This is likely the highest performance that can be expected from a computational approach, and further improvements may be difficult to reach. We further offer the medicinal scientist a PCA model to guide in vitro and/or in vivo studies to help limit the use of resources via very rapid computations.