A probabilistic method to report predictions from a human liver microsomes stability QSAR model: a practical tool for drug discovery

作者：Aliagas Ignacio^*; Gobbi Alberto; Heffron Timothy; Lee Man Ling; Ortwine Daniel F; Zak Mark; Khojasteh S Cyrus

来源：Journal of Computer-Aided Molecular Design, 2015, 29(4): 327-338.

DOI：10.1007/s10822-015-9838-3

• Liver microsomes
• In vitro clearance
• Probability
• QSAR model

Using data from the in vitro liver microsomes metabolic stability assay, we have developed QSAR models to predict in vitro human clearance. Models were trained using in house high-throughput assay data reported as the predicted human hepatic clearance by liver microsomes or pCL(h). Machine learning regression methods were used to generate the models. Model output for a given molecule was reported as its probability of being metabolically stable, thus allowing for synthesis prioritization based on this prediction. Use of probability, instead of the regression value or categories, has been found to be an efficient way for both reporting and assessing predictions. Model performance is evaluated using prospective validation. These models have been integrated into a number of desktop tools, and the models are routinely used to prioritize the synthesis of compounds. We discuss two therapeutic projects at Genentech that exemplify the benefits of a probabilistic approach in applying the models. A three-year retrospective analysis of measured liver microsomes stability data on all registered compounds at Genentech reveals that the use of these models has resulted in an improved metabolic stability profile of synthesized compounds.

• 出版日期2015-4